Role of Transforming Growth Factor-Beta (TGF) Beta in the Physiopathology of Rheumatoid Arthritis

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Efecto del TFG-β y moléculas implicadas en la diferenciación y regulación de las distintas poblaciones de células T efectoras en relación con su función dentro del sistema inmunitario. IL: interleucina; TGF-β: factor de crecimiento transformador beta; Treg: T reguladora." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elena Gonzalo-Gil, María Galindo-Izquierdo" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Elena" "apellidos" => "Gonzalo-Gil" ] 1 => array:2 [ "nombre" => "María" "apellidos" => "Galindo-Izquierdo" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S217357431400077X" "doi" => "10.1016/j.reumae.2014.01.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217357431400077X?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X14000345?idApp=UINPBA00004M" "url" => "/1699258X/0000001000000003/v1_201405040016/S1699258X14000345/v1_201405040016/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2173574313001330" "issn" => "21735743" "doi" => "10.1016/j.reumae.2013.12.002" "estado" => "S300" "fechaPublicacion" => "2014-05-01" "aid" => "571" "copyright" => "Elsevier España, S.L." 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Effect of TGF–β and molecules involved in the differentiation and regulation of the different populations of effector T cells in relation to their role in the immune system. IL, interleukin; TGF–β, transforming growth factor-beta; Treg, regulatory T cells." ] ] ] "textoCompleto" => "IntroductionRheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by chronic inflammation that affects diarthrodial joints, has a progressive course and causes joint functional disability, deformity and, ultimately, a decreased quality of life and reduced life expectancy. Its pathogenesis is characterized by an alteration of cellular and humoral immunity, and impaired resident cell components of the connective tissue of the synovial membrane (SM), which behave in a pseudotumoral fashion, invading and destroying adjacent tissue. The first manifestations of RA joint inflammatory response appear to be due to microvascular changes and an increase in the number of cells or synovial lining hyperplasia. These changes are accompanied by an altered regulation of cytokines, an increase in the number of fibroblasts and excess proliferation of inflammatory cells,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> mainly macrophages and lymphocytes, tissue destruction and angiogenesis.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Rheumatoid mesenchymal fibroblasts secrete proinflammatory cytokines and angiogenic growth factors which recruit synovial cells to the synovial space.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> By microarray analysis two subsets of fibroblasts have been identified in the rheumatoid SMIn, the inflamed tissue where there is an overexpression of a cell subtype that synthesizes transforming growth factor-beta (TGF–β) and Activin-A inducible gene, both characteristic of myofibroblasts. The other subgroup expresses genes regulated by insulin-like growth factor (IGF) and appears in less inflamed synovial membranes.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Activated macrophages are the major producers of inflammatory cytokines, including tumor necrosis factor-alpha (TNF–α). This, in turn, induce the release of other inflammatory cytokines such as interleukin (IL)-1, IL-6 or IL-8, involved in angiogenesis and the proliferation of the synovial fibroblasts and the production of factor platelet-derived growth (PDGF), fibroblast growth factor (FGF) and TGF–β. The sustained activation of these cell types leads to RA's structural alterations. Synovial macrophages, along with SF, play an important role in the tissue destruction characteristic of RA and are the main source of production of metalloproteinases (MMP). This phenomenon is directly regulated by proinflammatory cytokines such as IL-1, TNF–α, and TGF–β secreted in turn by resident macrophages in the synovium. Neutrophils are the most abundant cell type in the synovial fluid and capable of synthesizing TGF–β and IL-8, essential mediators in their own recruitment, establishing an autocrine circuit. In addition to cellular components, soluble factors of the rheumatoid synovial as well as certain proinflammatory cytokines (TNF–α, IL-1, IL-6, IL-17) are involved in activating osteoclastogenesis directly through osteoclast precursors.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> It has recently been discovered that the osteoclasts secrete IL-10, TGF–β and IL-6 and may act as antigen presenting cells and activate T CD8+ and CD4+ cells.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Angiogenesis is a remarkably active process in RA, especially in early stages and is regulated by various pro-angiogenic mediators such as TGF–β, angiopoietin, placenta growth factor, FGF, and vascular growth factor (VEGF). These factors activate endothelial cells and induce the production of proteolytic enzymes that degrade the basement membrane and perivascular extracellular matrix.In the rheumatoid synovium the expression of 4 growth factors has been described, TGF–β, PDGF, FGF and IGF.<a class="elsevierStyleCrossRefs" href="#bib0045">9,10</a> TGF-β is a homodimeric protein involved in the control of many biological processes such as angiogenesis, cell proliferation, differentiation, migration and apoptosis.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> This cytokine has a structure consisting of two disulfide-linked subunits, forming a homodimer of 25kDa. In mammals there are three isoforms of TGF–β (β TGF-1, TGF-2 and TGF–β 3) with similar functions but expressed in different tissues. TGF-β 3 has been detected mainly in cells of mesenchymal origin, indicating a different role of TGF–β 1 and 2. Lymphoid cells mainly produce the TGF–β 1 isoform, hence giving it a greater role in the immune system,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> particularly in the control of proliferation, activation and differentiation of T cells. So far, 3 receptors have been described, TGF–β (TGF–β RI, TGF-RII and TGF–β RIII), but the first 2 are the mediators of the biological responses of TGF–β 1.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>Role of Transforming Growth Factor-Beta in Rheumatoid ArthritisThe role of TGF–β has been studied in various models of disease, such as embryonic defects, cancer, autoimmune diseases, atherosclerosis, hypertension, osteoporosis and<a class="elsevierStyleCrossRef" href="#bib0070">14</a> fibrosing and inflammatory diseases. Numerous studies in fibrosis models have demonstrated the beneficial effect of blocking TGF–β<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> with antibody-specific anti-TGF-β antisense oligonucleotides,<a class="elsevierStyleCrossRefs" href="#bib0085">17,18</a> or synthetic peptides,<a class="elsevierStyleCrossRefs" href="#bib0095">19–21</a> demonstrating the role of TGF–β as a profibrotic agent. Other studies have shown that in late stages of tumor progression TGF–β promotes tumorigenesis and induces changes in the differentiation of epithelial tumor cells, a phenomenon known as epithelial–mesenchymal transdifferentiation.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Genetically modified animal models demonstrate the modulating effect of TGF–β on the immune response. Mice deficient in TGF–β 2 and TGF–β 3 have some defects that are lethal in embryonic development. However, mutations of TGF–β 1 gives rise to serious inflammatory disorders and multiorgan tissue necrosis which rapidly generates prenatal lethality (between 3 and 5 weeks old).<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Also, the functional absence of TGF–β 1 causes an accumulation of cells and pro-inflammatory cytokines (TNF–α, IFN-γ, IL-1 β) in the lymphoid organs, increased production of antigens of the major histocompatibility complex class I and II and a deficit in the proliferation of hematopoietic and endothelial cells.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Histologically, these mice showed massive infiltration of lymphocytes and macrophages, mainly in the lungs and heart, but are also found in muscle, liver, pancreas and brain, among other organs.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> These mice also exhibit anti-dsDNA, anti-ssDNA and glomerular deposition of immune antibodies. Other experiments have shown that mice transgenic for TGF–β RII (dnTRII β, which express TGF–β RII kinase with an incomplete intracellular domain under a specific promoter for T cells and, therefore, no signaling through the receptor) showed increased susceptibility to arthritis in comparison with WT phenotype mice, accompanied by an increase in the production of TNF-α and IFN–γ T cells in lymphoid nodes.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>Unlike what happens in other diseases where the role of TGF–β is well defined, studies in models of arthritis have exhibited very differing results (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Multiple studies have reported that intraperitoneal administration of TGF–β 1 will reduce the incidence and severity of arthritis in mice with collagen-induced arthritis (CIA), especially if the injection is made in late stages of the disease.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> In rats with arthritis due to Streptococcus (SCW) the intraperitoneal administration of TGF–β in the acute phase suppresses the development of arthritis.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> The same applies with the administration of TGF–β intramuscularly,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> but this is only seen if performed at the peak of inflammation. A very recent study has shown that mesenchymal stem cells derived from bone marrow and induced with TGF–β decrease the incidence and severity of arthritis in CIA mice with established disease. Also, they increase the proportion of Foxp3/IL-17 in the spleen and the peritoneal cavity, and reduce the production of pro-inflammatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> Another study in CIA mice showed a significant increase of TGF-β 1 and TGF–β 2 in the joint,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> particularly during the remission phase, indicating that both cytokines are involved in regulating the activity of the disease. In this regard, it has been shown that both the local or intraperitoneal injection of anti–TGF–β in mice with arthritis increases disease severity and proinflammatory cytokine levels.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>However, there are also many studies that exhibit a completely opposite role of TGF–β. In fact, repeated injections of TGF–β 1 in the healthy mice induced joint inflammation and synovial hyperplasia.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> Similarly, joint injection of TGF–β 1 in rats induces neutrophil recruitment, erythema, synovial proliferation and infiltration, mainly by T lymphocytes.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a> Several studies support this concept of TGF–β as a proinflammatory agent. Treatment with anti–TGF–β antibodies directly into the joint of rats with arthritis induced through a SCW model inhibits synovial inflammation, bone resorption and the production of proinflammatory cytokines.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> Other authors have shown that treatment with anti-TGF-β RI-antibodies induced arthritis in mice with anti-collagen Ab prevents arthritis, the development of hyperplasia, synovial inflammation and angiogenesis.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Among the therapeutic strategies described in the literature to block TGF–β specifically, p17 is of note.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> A study recently published by our group demonstrated that selective blockade of TGF–β with p17 moderately slows the signs of arthritis in the mouse model of CIA. However, this blockade has no effect on the differentiation and functionality of different populations of T cells, cytokines or the degree of osteocartilaginous destruction and concluded that TGF–β does not have a role in the CIA mouse model.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>The role of TGF–β differentiation of murine T cells has been extensively studied. In mice, it has been demonstrated that the specific overexpression of TGF–β in T cells leads to the generation of T cells with regulatory function and protects mice deficient in IL-2 for the development of severe systemic inflammation and autoimmunity.<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a> In the CIA model, Treg cell transfer at the time of immunization reduces the severity of arthritis.<a class="elsevierStyleCrossRefs" href="#bib0210">42,43</a> However, the role of TGF–β in the differentiation of Th17 cells is not completely defined. Initially, it was reported that TGF–β and IL-6, through the induction of IL-21, were able to promote T α β CD4+ naïve cell differentiation into Th17 cells via activation of the transducer factor signal STAT-3 and transcription factors Ror-gamma t and Ror α γ.<a class="elsevierStyleCrossRefs" href="#bib0220">44,45</a> Other studies have shown that IL-21, a member of the family of IL-2 cytokines, cooperates with TGF–β to induce differentiation of Th17 cells even in the absence of IL-6,<a class="elsevierStyleCrossRefs" href="#bib0230">46,47</a> while IL-23, produced by activated dendritic cells induces the survival and expansion of previously differentiated Th17 cells.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> However, a recent study demonstrated that the differentiation of Th17 cells in a murine model of experimental allergic encephalitis (EAE) can occur in the absence of TGF–β and in the presence of IL-6, IL-23 and IL-1 β,<a class="elsevierStyleCrossRef" href="#bib0245">49</a> similar to that originally proposed in humans. These Th17 cells induced by IL-23 coexpress with a pathogenic phenotype γ Ror-gamma t and T-bet and can result in γ IL-17/IFN-producing cells, unlike Th17 cells induced by TGF–β, considered as non-pathogenic. Other authors have suggested that TGF–β does not act directly to promote differentiation of murine Th17 cells, but acts indirectly to regulate IL-17 by removal of the factors that contribute to the differentiation of Th1 and Th2 cells.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Very recently it has been reported that Th17 cells developed by a mechanism dependent on IL-23, IL-6 and TGF–β 1 are pathogenic and produce large amounts of TGF–β 3.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> In addition, TGF–β 3 Th17 cells have a pathogenic role in EAE models of colitis, similar to the pathogenicity of Th17 differentiated in the presence of IL-6 and TGF–β 1 and produce higher amounts of IL-23. Moreover, CD8 + T cells in the rheumatoid synovium induce the synthesis of IFN–γ and IL-17, and have demonstrated their role in a chronic synovitis model K/BxN mouse.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> TGF-β acts on CD8+ cells, inducing the production of Foxp3 and IL-17, resulting in CD8+ Treg and CD8+ IL-17+, respectively.<a class="elsevierStyleCrossRefs" href="#bib0265">53,54</a> However, its role in triggering CIA<a class="elsevierStyleCrossRefs" href="#bib0275">55,56</a> shows mixed results, indicating that these cells may not be involved in the onset of disease.The role of TGF–β in animal models of RA, therefore, is not well defined and the discrepancy in the results for effect on the different cell types in the rheumatoid synovium indicate an impairment of the factors responsible for the Smad protein dependent intracellular pathway. These changes result in abnormal responses of TGF–β, conditioning altered cell behavior. Smad-3−/− animals exhibit an exaggerated inflammatory response, while the deficit of Smad-2−/− is lethal due to defects in embryonic development.<a class="elsevierStyleCrossRef" href="#bib0285">57</a> Also, transgenic mice for Smad-7 are associated with increased production of cytokines by T helper (Th) 1 and Th2 cells. Some authors have reported that Smad-2 is significantly reduced in the cartilage during the progression of osteoarthritis (OA) in several animal models,<a class="elsevierStyleCrossRef" href="#bib0290">58</a> while other studies show an increase in the expression of TGF-RII β and synovial fibroblasts of RA patients compared with OA patients.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>In humans, almost all the cellular components of the rheumatoid synovium may secrete TGF–β and besides exerting action on mesenchymal cells, this cytokine plays a modulatory effect on inflammatory cells. In in vitro studies with cells of the rheumatoid synovium TGF–β dependent effects are disparate, behaving as immunoregulatory inducer or inhibitor factor of the inflammatory response according to the surrounding conditions. Among the anti-inflammatory effects, the inhibition of lymphocyte proliferation and superoxide production by macrophages are included.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> However, it can also act as a proinflammatory factor in stimulating the secretion of cytokines such as TNF–α and IL-1, acting as a potent chemoattractant for neutrophils, activating the expression of chemokines, MMP and,<a class="elsevierStyleCrossRefs" href="#bib0305">61,62</a> inducing expression of VEGF,<a class="elsevierStyleCrossRef" href="#bib0315">63</a> essential in the development of angiogenesis in RA, and modulating apoptosis of SF in a poorly defined mechanism. In this regard, TGF–β inhibits Fas expression and increases Bcl-2 and proto-Bclx, although other authors suggested PI3K and Akt activation as responsible for the antiapoptotic effect of TGF–β.<a class="elsevierStyleCrossRef" href="#bib0320">64</a>The mononuclear cells from rheumatoid synovial tissue in culture produce β TGF-1 and its presence has been demonstrated in the synovial tissue and fluid.<a class="elsevierStyleCrossRef" href="#bib0325">65</a> Microarray studies suggest an increase in the TGF-signaling pathway in SF-β of RA patients as compared to patients with OA, in particular TGF-1 and its receptor β (TGF–β RI), accompanied by an increased expression of MMP. This increased TGF–β 1 expression correlates directly with clinical markers of disease activity such as C-reactive protein serum activity and ACR<a class="elsevierStyleCrossRef" href="#bib0330">66</a> criteria, indicating a direct correlation between TGF-1 and inflammation β. In this sense, the described activation of TGF–β signaling pathways in mononuclear cells in rheumatoid inflammatory aggregates indicates a possible pathogenetic involvement of this cytokine in the development of the disease.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>The SM in RA contains lots of T<a class="elsevierStyleCrossRef" href="#bib0335">67</a> cells. However, it has been difficult to define the role these play in the maintenance and propagation of joint inflammation. The use in the treatment of RA of a fusion protein of human CTLA-4 inhibiting T cell costimulation via CD28 has provided an indirect but convincing evidence for the importance of T cells in RA.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> The role of TGF–β in differentiating different populations of human T cells is manifold. On one hand, it has been shown that signaling through TGF–β 1 protects regulatory T (Treg) cells from apoptosis<a class="elsevierStyleCrossRef" href="#bib0345">69</a> and is absolutely necessary to induce the expression of Foxp3, as it has been shown that impaired CD4+ cells due to lack of TGF–β 1 can not generate Treg cells in vivo and in vitro.<a class="elsevierStyleCrossRefs" href="#bib0350">70–73</a> Treg cells can develop from thymic CD4+ T cell precursors in the presence of TGF–β and IL-2, resulting in natural Treg cells. In the periphery, the naïve CD4+ cells can become inducible Treg cells via STAT signaling-5 in the presence of TGF–β, increasing Foxp3 expression (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The Foxp3 promoter regulation depends on, among other things, on the NF-AT transcription factor and Smad-3 signaling induced by TGF–β.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> In fact, TGF–β mediates Foxp3 expression by directly binding to the promoter of Smad. Treg cells secrete low amounts of IL-2 and IFN–γ, while producing high amounts of IL-10, IL-35 and TGF–β, essential to regulate the suppression of T cells.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> Recently, it has been described that, in the absence of TGF–β1, functional development of Treg in cancer cells could be produced by a compensatory mechanism dependent on the expression of TGF-β 2 and TGF–β 3 in the thymus and periphery.<a class="elsevierStyleCrossRefs" href="#bib0380">76,77</a> However, it is unknown whether this mechanism occurs in RA.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Classically, it was assumed that RA was a disease mediated by Th1 cells producing IFN–γ in the absence of Th2 cytokines. In the differentiation of both cell types, TGF–β acts as a negative regulator by inhibiting T-bet and GATA-3 transcription factors,<a class="elsevierStyleCrossRefs" href="#bib0390">78,79</a> respectively. However, over the past 10 years, it has become increasingly important as Th17 cells promote the inflammatory response in RA. In human Th17 differentiation, several mechanisms may be involved. First, it was determined that the differentiation of human Th17 cells occurred in the absence of TGF–β<a class="elsevierStyleCrossRef" href="#bib0400">80</a> and that the combination of IL-1 β, IL-6 and IL-23 was able to act on memory T cells to produce IL-17. However, other studies disclose a role for TGF–β, which together with IL-21 and expression of Rorc2 promote differentiation of naïve CD4+ to Th17 cells.<a class="elsevierStyleCrossRef" href="#bib0405">81</a> In this regard, TGF–β through IL-21 suppresses the induction of T-bet. Recent studies point to an interaction of mesenchymal stem cells derived from bone marrow or synovial fibroblasts with T cells as promoting activation and expansion of Th17 cells, which may contribute to the chronicity of RA.<a class="elsevierStyleCrossRef" href="#bib0410">82</a> Recently, we have described a new subtype of Th cells, Th9, producing IL-9 and IL-10. The differentiation of these cells from naïve T cells is TGF–β and IL-4 dependent,<a class="elsevierStyleCrossRef" href="#bib0415">83</a> although the treatment of Th2 cells with TGF–β is also capable of producing Th9 cells. In spite of the production of IL-10, when not expressing Foxp3, they are not considered regulatory cells, but inflammation-promoting cells. In fact, although its role in RA has not been investigated in other models of inflammatory disease, such as EAE, it has been noted that they can act as inducers of inflammation.<a class="elsevierStyleCrossRef" href="#bib0420">84</a> It has also been shown that the stimulation with TGF–β and IL-1-induced CD4 β IL-9+/+ IL-17 in patients with autoimmune diabetes,<a class="elsevierStyleCrossRef" href="#bib0425">85</a> hence it has a possible role in other autoimmune diseases.ConclusionTGF-β is a cytokine involved in numerous biological processes. Of the 3 isoforms of TGF–β that exist in mammals, TGF–β 1 plays the most important role in the immune system, particularly in the control of proliferation, activation and differentiation of T cells; one study to try to define the role of TGF–β in RA have shown mixed findings. The differences of these findings could be due to the animal model used, the time since onset of the disease in the study and the protocol used for inhibition of the cytokine.Ethical ResponsibilitiesProtection of people and animalsThe authors declare that this research has not performed experiments on humans or animals.Data privacyThe authors state that patient data does not appear in this article.Right to privacy and informed consentThe authors state that no patient data appears in this article.FinancingThis project was funded by a grant from the Spanish Foundation of Rheumatology (FER 2009) in the form of aid for research projects not funded by public agencies. Elena Gonzalo Gil has received funding from a grant from the Spanish Foundation of Rheumatology (FER) in the form of aid to supplement research projects already funded.Conflicts of InterestThe authors have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres346852" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec328515" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres346853" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec328514" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Role of Transforming Growth Factor-Beta in Rheumatoid Arthritis" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Conclusion" ] 7 => array:3 [ "identificador" => "sec0050" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Protection of people and animals" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Data privacy" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Right to privacy and informed consent" ] ] ] 8 => array:2 [ "identificador" => "sec0020" "titulo" => "Financing" ] 9 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflicts of Interest" ] 10 => array:2 [ "identificador" => "xack85415" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-10-18" "fechaAceptado" => "2014-01-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec328515" "palabras" => array:5 [ 0 => "Rheumatoid arthritis" 1 => "Animal models" 2 => "Collagen-induced arthritis" 3 => "Transforming growth factor-beta" 4 => "T cells" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec328514" "palabras" => array:5 [ 0 => "Artritis reumatoide" 1 => "Modelos animales" 2 => "Artritis-inducida con colágeno" 3 => "Factor de crecimiento transformador-beta" 4 => "Células T" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "TGF-β is a cytokine with pleiotropic functions in hematopoiesis, angiogenesis, cell proliferation, differentiation, migration and apoptosis. Although its role in rheumatoid arthritis is not well defined, TGF-β activation leads to functional immunomodulatory effects according to environmental conditions. The function of TGF-β in the development of arthritis in murine models has been extensively studied with controversial results. Recent findings point to a non-relevant role for TGF-β in a mice model of collagen-induced arthritis. The study of TGF-β on T-cell responses has shown controversial results as an inhibitor or promoter of the inflammatory response. This paper presents a review of the role of TGF-β in animal models of arthritis." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El TGF-β es una citocina implicada en procesos celulares como hematopoyesis, proliferación, angiogénesis, diferenciación, migración y apoptosis celular. Aunque su papel en la artritis reumatoide no está bien definido, está considerada como una citocina inmunomoduladora según las condiciones del entorno. Numerosos trabajos han tratado de definir el papel del TGF-β en el desarrollo de la artritis murina en diferentes modelos de enfermedad, con resultados discordantes. De hecho, resultados recientemente publicados indican que TGF-β no desempeña un papel relevante en el modelo murino de artritis inducida con colágeno. Su implicación en la diferenciación y la funcionalidad de las diferentes poblaciones de células T también ha mostrado resultados dispares sobre su papel como inhibidor o promotor de la respuesta inflamatoria. En este trabajo se presenta una revisión sobre el papel de TGF-β en modelos animales de artritis." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Gonzalo-Gil E, Galindo-Izquierdo M. Papel del factor de crecimiento transformador-beta (TGF-β) en la fisiopatología de la artritis reumatoide. Reumatol Clin. 2014;10:174–179." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2232 "Ancho" => 3001 "Tamanyo" => 449958 ] ] "descripcion" => array:1 [ "en" => "Role of TGF–β in the differentiation of effector T cells. Effect of TGF–β and molecules involved in the differentiation and regulation of the different populations of effector T cells in relation to their role in the immune system. IL, interleukin; TGF–β, transforming growth factor-beta; Treg, regulatory T cells." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "Ab, antibodies; CAIA, arthritis induced with anti-collagen antibodies; CIA, collagen-induced arthritis; TGF–β 1, transforming growth factor-beta 1; IP, intraperitoneal; SCW, arthritis induced by Streptococcus." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Animal modelAnti-inflammatory effect \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Animal modelProinflammatory effect \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Administration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Ref. \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mice with CIARats with SCW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGF–β 1 IP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0130">26–28</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mice with CIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mesenchymal cells, TGF–β IP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0150">30</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mice with CIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-TGF–β local and IP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Healthy mice and rats \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGF–β 1 local \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0170">34–36</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rats with SCW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-TGF–β local \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0185">37</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mice with CAIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-TGF–β RI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0010">2</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab517366.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Role of TGF–β in Animal Models of Arthritis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:85 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Fibroblast biology. 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Role of Transforming Growth Factor-Beta (TGF) Beta in the Physiopathology of Rheumatoid Arthritis

Papel del factor de crecimiento transformador-beta (TGF-β) en la fisiopatología de la artritis reumatoide

Elena Gonzalo-Gil, María Galindo-Izquierdo

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mgalindo@h12o.es

Corresponding author.

Laboratorio de Enfermedades Inflamatorias y Autoinmunes, Instituto de Investigación, «i+12», Hospital 12 de Octubre, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Rheumatoid arthritis &#40;RA&#41; is an autoimmune disease of unknown etiology&#44; characterized by chronic inflammation that affects diarthrodial joints&#44; has a progressive course and causes joint functional disability&#44; deformity and&#44; ultimately&#44; a decreased quality of life and reduced life expectancy&#46; Its pathogenesis is characterized by an alteration of cellular and humoral immunity&#44; and impaired resident cell components of the connective tissue of the synovial membrane &#40;SM&#41;&#44; which behave in a pseudotumoral fashion&#44; invading and destroying adjacent tissue&#46; The first manifestations of RA joint inflammatory response appear to be due to microvascular changes and an increase in the number of cells or synovial <span class="elsevierStyleItalic">lining</span> hyperplasia&#46; These changes are accompanied by an altered regulation of cytokines&#44; an increase in the number of fibroblasts and excess proliferation of inflammatory cells&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> mainly macrophages and lymphocytes&#44; tissue destruction and angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Rheumatoid mesenchymal fibroblasts secrete proinflammatory cytokines and angiogenic growth factors which recruit synovial cells to the synovial space&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> By microarray analysis two subsets of fibroblasts have been identified in the rheumatoid SMIn&#44; the inflamed tissue where there is an overexpression of a cell subtype that synthesizes transforming growth factor-beta &#40;TGF&#8211;&#946;&#41; and Activin-A inducible gene&#44; both characteristic of myofibroblasts&#46; The other subgroup expresses genes regulated by insulin-like growth factor &#40;IGF&#41; and appears in less inflamed synovial membranes&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Activated macrophages are the major producers of inflammatory cytokines&#44; including tumor necrosis factor-alpha &#40;TNF&#8211;&#945;&#41;&#46; This&#44; in turn&#44; induce the release of other inflammatory cytokines such as interleukin &#40;IL&#41;-1&#44; IL-6 or IL-8&#44; involved in angiogenesis and the proliferation of the synovial fibroblasts and the production of factor platelet-derived growth &#40;PDGF&#41;&#44; fibroblast growth factor &#40;FGF&#41; and TGF&#8211;&#946;&#46; The sustained activation of these cell types leads to RA&#39;s structural alterations&#46; Synovial macrophages&#44; along with SF&#44; play an important role in the tissue destruction characteristic of RA and are the main source of production of metalloproteinases &#40;MMP&#41;&#46; This phenomenon is directly regulated by proinflammatory cytokines such as IL-1&#44; TNF&#8211;&#945;&#44; and TGF&#8211;&#946; secreted in turn by resident macrophages in the synovium&#46; Neutrophils are the most abundant cell type in the synovial fluid and capable of synthesizing TGF&#8211;&#946; and IL-8&#44; essential mediators in their own recruitment&#44; establishing an autocrine circuit&#46; In addition to cellular components&#44; soluble factors of the rheumatoid synovial as well as certain proinflammatory cytokines &#40;TNF&#8211;&#945;&#44; IL-1&#44; IL-6&#44; IL-17&#41; are involved in activating osteoclastogenesis directly through osteoclast precursors&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> It has recently been discovered that the osteoclasts secrete IL-10&#44; TGF&#8211;&#946; and IL-6 and may act as antigen presenting cells and activate T CD8&#43; and CD4&#43; cells&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Angiogenesis is a remarkably active process in RA&#44; especially in early stages and is regulated by various pro-angiogenic mediators such as TGF&#8211;&#946;&#44; angiopoietin&#44; placenta growth factor&#44; FGF&#44; and vascular growth factor &#40;VEGF&#41;&#46; These factors activate endothelial cells and induce the production of proteolytic enzymes that degrade the basement membrane and perivascular extracellular matrix&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In the rheumatoid synovium the expression of 4 growth factors has been described&#44; TGF&#8211;&#946;&#44; PDGF&#44; FGF and IGF&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10</span></a> TGF-&#946; is a homodimeric protein involved in the control of many biological processes such as angiogenesis&#44; cell proliferation&#44; differentiation&#44; migration and apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> This cytokine has a structure consisting of two disulfide-linked subunits&#44; forming a homodimer of 25<span class="elsevierStyleHsp" style=""></span>kDa&#46; In mammals there are three isoforms of TGF&#8211;&#946; &#40;&#946; TGF-1&#44; TGF-2 and TGF&#8211;&#946; 3&#41; with similar functions but expressed in different tissues&#46; TGF-&#946; 3 has been detected mainly in cells of mesenchymal origin&#44; indicating a different role of TGF&#8211;&#946; 1 and 2&#46; Lymphoid cells mainly produce the TGF&#8211;&#946; 1 isoform&#44; hence giving it a greater role in the immune system&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> particularly in the control of proliferation&#44; activation and differentiation of T cells&#46; So far&#44; 3 receptors have been described&#44; TGF&#8211;&#946; &#40;TGF&#8211;&#946; RI&#44; TGF-RII and TGF&#8211;&#946; RIII&#41;&#44; but the first 2 are the mediators of the biological responses of TGF&#8211;&#946; 1&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Role of Transforming Growth Factor-Beta in Rheumatoid Arthritis</span><p id="par0020" class="elsevierStylePara elsevierViewall">The role of TGF&#8211;&#946; has been studied in various models of disease&#44; such as embryonic defects&#44; cancer&#44; autoimmune diseases&#44; atherosclerosis&#44; hypertension&#44; osteoporosis and<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> fibrosing and inflammatory diseases&#46; Numerous studies in fibrosis models have demonstrated the beneficial effect of blocking TGF&#8211;&#946;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> with antibody-specific anti-TGF-&#946; antisense oligonucleotides&#44;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> or synthetic peptides&#44;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#8211;21</span></a> demonstrating the role of TGF&#8211;&#946; as a profibrotic agent&#46; Other studies have shown that in late stages of tumor progression TGF&#8211;&#946; promotes tumorigenesis and induces changes in the differentiation of epithelial tumor cells&#44; a phenomenon known as epithelial&#8211;mesenchymal transdifferentiation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Genetically modified animal models demonstrate the modulating effect of TGF&#8211;&#946; on the immune response&#46; Mice deficient in TGF&#8211;&#946; 2 and TGF&#8211;&#946; 3 have some defects that are lethal in embryonic development&#46; However&#44; mutations of TGF&#8211;&#946; 1 gives rise to serious inflammatory disorders and multiorgan tissue necrosis which rapidly generates prenatal lethality &#40;between 3 and 5 weeks old&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Also&#44; the functional absence of TGF&#8211;&#946; 1 causes an accumulation of cells and pro-inflammatory cytokines &#40;TNF&#8211;&#945;&#44; IFN-&#947;&#44; IL-1 &#946;&#41; in the lymphoid organs&#44; increased production of antigens of the major histocompatibility complex class <span class="elsevierStyleSmallCaps">I</span> and <span class="elsevierStyleSmallCaps">II</span> and a deficit in the proliferation of hematopoietic and endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Histologically&#44; these mice showed massive infiltration of lymphocytes and macrophages&#44; mainly in the lungs and heart&#44; but are also found in muscle&#44; liver&#44; pancreas and brain&#44; among other organs&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> These mice also exhibit anti-dsDNA&#44; anti-ssDNA and glomerular deposition of immune antibodies&#46; Other experiments have shown that mice transgenic for TGF&#8211;&#946; RII &#40;dnTRII &#946;&#44; which express TGF&#8211;&#946; RII kinase with an incomplete intracellular domain under a specific promoter for T cells and&#44; therefore&#44; no signaling through the receptor&#41; showed increased susceptibility to arthritis in comparison with WT phenotype mice&#44; accompanied by an increase in the production of TNF-&#945; and IFN&#8211;&#947; T cells in lymphoid nodes&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Unlike what happens in other diseases where the role of TGF&#8211;&#946; is well defined&#44; studies in models of arthritis have exhibited very differing results &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Multiple studies have reported that intraperitoneal administration of TGF&#8211;&#946; 1 will reduce the incidence and severity of arthritis in mice with collagen-induced arthritis &#40;CIA&#41;&#44; especially if the injection is made in late stages of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> In rats with arthritis due to <span class="elsevierStyleItalic">Streptococcus</span> &#40;SCW&#41; the intraperitoneal administration of TGF&#8211;&#946; in the acute phase suppresses the development of arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The same applies with the administration of TGF&#8211;&#946; intramuscularly&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> but this is only seen if performed at the peak of inflammation&#46; A very recent study has shown that mesenchymal stem cells derived from bone marrow and induced with TGF&#8211;&#946; decrease the incidence and severity of arthritis in CIA mice with established disease&#46; Also&#44; they increase the proportion of Foxp3&#47;IL-17 in the spleen and the peritoneal cavity&#44; and reduce the production of pro-inflammatory cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Another study in CIA mice showed a significant increase of TGF-&#946; 1 and TGF&#8211;&#946; 2 in the joint&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> particularly during the remission phase&#44; indicating that both cytokines are involved in regulating the activity of the disease&#46; In this regard&#44; it has been shown that both the local or intraperitoneal injection of anti&#8211;TGF&#8211;&#946; in mice with arthritis increases disease severity and proinflammatory cytokine levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">However&#44; there are also many studies that exhibit a completely opposite role of TGF&#8211;&#946;&#46; In fact&#44; repeated injections of TGF&#8211;&#946; 1 in the healthy mice induced joint inflammation and synovial hyperplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Similarly&#44; joint injection of TGF&#8211;&#946; 1 in rats induces neutrophil recruitment&#44; erythema&#44; synovial proliferation and infiltration&#44; mainly by T lymphocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> Several studies support this concept of TGF&#8211;&#946; as a proinflammatory agent&#46; Treatment with anti&#8211;TGF&#8211;&#946; antibodies directly into the joint of rats with arthritis induced through a SCW model inhibits synovial inflammation&#44; bone resorption and the production of proinflammatory cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Other authors have shown that treatment with anti-TGF-&#946; RI-antibodies induced arthritis in mice with anti-collagen Ab prevents arthritis&#44; the development of hyperplasia&#44; synovial inflammation and angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Among the therapeutic strategies described in the literature to block TGF&#8211;&#946; specifically&#44; p17 is of note&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> A study recently published by our group demonstrated that selective blockade of TGF&#8211;&#946; with p17 moderately slows the signs of arthritis in the mouse model of CIA&#46; However&#44; this blockade has no effect on the differentiation and functionality of different populations of T cells&#44; cytokines or the degree of osteocartilaginous destruction and concluded that TGF&#8211;&#946; does not have a role in the CIA mouse model&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The role of TGF&#8211;&#946; differentiation of murine T cells has been extensively studied&#46; In mice&#44; it has been demonstrated that the specific overexpression of TGF&#8211;&#946; in T cells leads to the generation of T cells with regulatory function and protects mice deficient in IL-2 for the development of severe systemic inflammation and autoimmunity&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> In the CIA model&#44; Treg cell transfer at the time of immunization reduces the severity of arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a> However&#44; the role of TGF&#8211;&#946; in the differentiation of Th17 cells is not completely defined&#46; Initially&#44; it was reported that TGF&#8211;&#946; and IL-6&#44; through the induction of IL-21&#44; were able to promote T &#945; &#946; CD4&#43; <span class="elsevierStyleItalic">na&#239;ve cell differentiation into</span> Th17 cells <span class="elsevierStyleItalic">via</span> activation of the transducer factor signal STAT-3 and transcription factors Ror-gamma t and Ror &#945; &#947;&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#44;45</span></a> Other studies have shown that IL-21&#44; a member of the family of IL-2 cytokines&#44; cooperates with TGF&#8211;&#946; to induce differentiation of Th17 cells even in the absence of IL-6&#44;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a> while IL-23&#44; produced by activated dendritic cells induces the survival and expansion of previously differentiated Th17 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> However&#44; a recent study demonstrated that the differentiation of Th17 cells in a murine model of experimental allergic encephalitis &#40;EAE&#41; can occur in the absence of TGF&#8211;&#946; and in the presence of IL-6&#44; IL-23 and IL-1 &#946;&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> similar to that originally proposed in humans&#46; These Th17 cells induced by IL-23 coexpress with a pathogenic phenotype &#947; Ror-gamma t and T-bet and can result in &#947; IL-17&#47;IFN-producing cells&#44; unlike Th17 cells induced by TGF&#8211;&#946;&#44; considered as non-pathogenic&#46; Other authors have suggested that TGF&#8211;&#946; does not act directly to promote differentiation of murine Th17 cells&#44; but acts indirectly to regulate IL-17 by removal of the factors that contribute to the differentiation of Th1 and Th2 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Very recently it has been reported that Th17 cells developed by a mechanism dependent on IL-23&#44; IL-6 and TGF&#8211;&#946; 1 are pathogenic and produce large amounts of TGF&#8211;&#946; 3&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> In addition&#44; TGF&#8211;&#946; 3 Th17 cells have a pathogenic role in EAE models of colitis&#44; similar to the pathogenicity of Th17 differentiated in the presence of IL-6 and TGF&#8211;&#946; 1 and produce higher amounts of IL-23&#46; Moreover&#44; CD8 &#43; T cells in the rheumatoid synovium induce the synthesis of IFN&#8211;&#947; and IL-17&#44; and have demonstrated their role in a chronic synovitis model K&#47;BxN mouse&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> TGF-&#946; acts on CD8&#43; cells&#44; inducing the production of Foxp3 and IL-17&#44; resulting in CD8&#43; Treg and CD8&#43; IL-17&#43;&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;54</span></a> However&#44; its role in triggering CIA<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#44;56</span></a> shows mixed results&#44; indicating that these cells may not be involved in the onset of disease&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The role of TGF&#8211;&#946; in animal models of RA&#44; therefore&#44; is not well defined and the discrepancy in the results for effect on the different cell types in the rheumatoid synovium indicate an impairment of the factors responsible for the Smad protein dependent intracellular pathway&#46; These changes result in abnormal responses of TGF&#8211;&#946;&#44; conditioning altered cell behavior&#46; Smad-3<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span> animals exhibit an exaggerated inflammatory response&#44; while the deficit of Smad-2<span class="elsevierStyleSup">&#8722;&#47;&#8722;</span> is lethal due to defects in embryonic development&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Also&#44; transgenic mice for Smad-7 are associated with increased production of cytokines by T helper &#40;Th&#41; 1 and Th2 cells&#46; Some authors have reported that Smad-2 is significantly reduced in the cartilage during the progression of osteoarthritis &#40;OA&#41; in several animal models&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> while other studies show an increase in the expression of TGF-RII &#946; and synovial fibroblasts of RA patients compared with OA patients&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In humans&#44; almost all the cellular components of the rheumatoid synovium may secrete TGF&#8211;&#946; and besides exerting action on mesenchymal cells&#44; this cytokine plays a modulatory effect on inflammatory cells&#46; In <span class="elsevierStyleItalic">in vitro</span> studies with cells of the rheumatoid synovium TGF&#8211;&#946; dependent effects are disparate&#44; behaving as immunoregulatory inducer or inhibitor factor of the inflammatory response according to the surrounding conditions&#46; Among the anti-inflammatory effects&#44; the inhibition of lymphocyte proliferation and superoxide production by macrophages are included&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> However&#44; it can also act as a proinflammatory factor in stimulating the secretion of cytokines such as TNF&#8211;&#945; and IL-1&#44; acting as a potent chemoattractant for neutrophils&#44; activating the expression of chemokines&#44; MMP and&#44;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a> inducing expression of VEGF&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> essential in the development of angiogenesis in RA&#44; and modulating apoptosis of SF in a poorly defined mechanism&#46; In this regard&#44; TGF&#8211;&#946; inhibits Fas expression and increases Bcl-2 and proto-Bclx&#44; although other authors suggested PI3K and Akt activation as responsible for the antiapoptotic effect of TGF&#8211;&#946;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">The mononuclear cells from rheumatoid synovial tissue in culture produce &#946; TGF-1 and its presence has been demonstrated in the synovial tissue and fluid&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> Microarray studies suggest an increase in the TGF-signaling pathway in SF-&#946; of RA patients as compared to patients with OA&#44; in particular TGF-1 and its receptor &#946; &#40;TGF&#8211;&#946; RI&#41;&#44; accompanied by an increased expression of MMP&#46; This increased TGF&#8211;&#946; 1 expression correlates directly with clinical markers of disease activity such as C-reactive protein serum activity and ACR<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> criteria&#44; indicating a direct correlation between TGF-1 and inflammation &#946;&#46; In this sense&#44; the described activation of TGF&#8211;&#946; signaling pathways in mononuclear cells in rheumatoid inflammatory aggregates indicates a possible pathogenetic involvement of this cytokine in the development of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The SM in RA contains lots of T<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> cells&#46; However&#44; it has been difficult to define the role these play in the maintenance and propagation of joint inflammation&#46; The use in the treatment of RA of a fusion protein of human CTLA-4 inhibiting T cell costimulation <span class="elsevierStyleItalic">via</span> CD28 has provided an indirect but convincing evidence for the importance of T cells in RA&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> The role of TGF&#8211;&#946; in differentiating different populations of human T cells is manifold&#46; On one hand&#44; it has been shown that signaling through TGF&#8211;&#946; 1 protects regulatory T &#40;Treg&#41; cells from apoptosis<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> and is absolutely necessary to induce the expression of Foxp3&#44; as it has been shown that impaired CD4&#43; cells due to lack of TGF&#8211;&#946; 1 can not generate Treg cells <span class="elsevierStyleItalic">in vivo</span> and <span class="elsevierStyleItalic">in vitro</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">70&#8211;73</span></a> Treg cells can develop from thymic CD4&#43; T cell precursors in the presence of TGF&#8211;&#946; and IL-2&#44; resulting in natural Treg cells&#46; In the periphery&#44; the <span class="elsevierStyleItalic">na&#239;ve</span> CD4&#43; cells can become inducible Treg cells <span class="elsevierStyleItalic">via</span> STAT signaling-5 in the presence of TGF&#8211;&#946;&#44; increasing Foxp3 expression &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The Foxp3 promoter regulation depends on&#44; among other things&#44; on the NF-AT transcription factor and Smad-3 signaling induced by TGF&#8211;&#946;&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> In fact&#44; TGF&#8211;&#946; mediates Foxp3 expression by directly binding to the promoter of Smad&#46; Treg cells secrete low amounts of IL-2 and IFN&#8211;&#947;&#44; while producing high amounts of IL-10&#44; IL-35 and TGF&#8211;&#946;&#44; essential to regulate the suppression of T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> Recently&#44; it has been described that&#44; in the absence of TGF&#8211;&#946;1&#44; functional development of Treg in cancer cells could be produced by a compensatory mechanism dependent on the expression of TGF-&#946; 2 and TGF&#8211;&#946; 3 in the thymus and periphery&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76&#44;77</span></a> However&#44; it is unknown whether this mechanism occurs in RA&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">Classically&#44; it was assumed that RA was a disease mediated by Th1 cells producing IFN&#8211;&#947; in the absence of Th2 cytokines&#46; In the differentiation of both cell types&#44; TGF&#8211;&#946; acts as a negative regulator by inhibiting T-bet and GATA-3 transcription factors&#44;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;79</span></a> respectively&#46; However&#44; over the past 10 years&#44; it has become increasingly important as Th17 cells promote the inflammatory response in RA&#46; In human Th17 differentiation&#44; several mechanisms may be involved&#46; First&#44; it was determined that the differentiation of human Th17 cells occurred in the absence of TGF&#8211;&#946;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> and that the combination of IL-1 &#946;&#44; IL-6 and IL-23 was able to act on memory T cells to produce IL-17&#46; However&#44; other studies disclose a role for TGF&#8211;&#946;&#44; which together with IL-21 and expression of Rorc2 promote differentiation of <span class="elsevierStyleItalic">na&#239;ve</span> CD4&#43; to Th17 cells&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> In this regard&#44; TGF&#8211;&#946; through IL-21 suppresses the induction of T-bet&#46; Recent studies point to an interaction of mesenchymal stem cells derived from bone marrow or synovial fibroblasts with T cells as promoting activation and expansion of Th17 cells&#44; which may contribute to the chronicity of RA&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> Recently&#44; we have described a new subtype of Th cells&#44; Th9&#44; producing IL-9 and IL-10&#46; The differentiation of these cells from <span class="elsevierStyleItalic">na&#239;ve</span> T cells is TGF&#8211;&#946; and IL-4 dependent&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a> although the treatment of Th2 cells with TGF&#8211;&#946; is also capable of producing Th9 cells&#46; In spite of the production of IL-10&#44; when not expressing Foxp3&#44; they are not considered regulatory cells&#44; but inflammation-promoting cells&#46; In fact&#44; although its role in RA has not been investigated in other models of inflammatory disease&#44; such as EAE&#44; it has been noted that they can act as inducers of inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">84</span></a> It has also been shown that the stimulation with TGF&#8211;&#946; and IL-1-induced CD4 &#946; IL-9<span class="elsevierStyleSup">&#43;&#47;&#43;</span> IL-17 in patients with autoimmune diabetes&#44;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">85</span></a> hence it has a possible role in other autoimmune diseases&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Conclusion</span><p id="par0070" class="elsevierStylePara elsevierViewall">TGF-&#946; is a cytokine involved in numerous biological processes&#46; Of the 3 isoforms of TGF&#8211;&#946; that exist in mammals&#44; TGF&#8211;&#946; 1 plays the most important role in the immune system&#44; particularly in the control of proliferation&#44; activation and differentiation of T cells&#59; one study to try to define the role of TGF&#8211;&#946; in RA have shown mixed findings&#46; The differences of these findings could be due to the animal model used&#44; the time since onset of the disease in the study and the protocol used for inhibition of the cytokine&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical Responsibilities</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of people and animals</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that this research has not performed experiments on humans or animals&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Data privacy</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors state that patient data does not appear in this article&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0115" class="elsevierStylePara elsevierViewall">The authors state that no patient data appears in this article&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Financing</span><p id="par0075" class="elsevierStylePara elsevierViewall">This project was funded by a grant from the Spanish Foundation of Rheumatology &#40;FER 2009&#41; in the form of aid for research projects not funded by public agencies&#46; Elena Gonzalo Gil has received funding from a grant from the Spanish Foundation of Rheumatology &#40;FER&#41; in the form of aid to supplement research projects already funded&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of Interest</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Abstract"
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          "titulo" => "Keywords"
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          "titulo" => "Palabras clave"
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          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Role of Transforming Growth Factor-Beta in Rheumatoid Arthritis"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Conclusion"
        ]
        7 => array:3 [
          "identificador" => "sec0050"
          "titulo" => "Ethical Responsibilities"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Protection of people and animals"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Data privacy"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Right to privacy and informed consent"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Financing"
        ]
        9 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conflicts of Interest"
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        10 => array:2 [
          "identificador" => "xack85415"
          "titulo" => "Acknowledgements"
        ]
        11 => array:1 [
          "titulo" => "References"
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      ]
    ]
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    "fechaRecibido" => "2013-10-18"
    "fechaAceptado" => "2014-01-21"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec328515"
          "palabras" => array:5 [
            0 => "Rheumatoid arthritis"
            1 => "Animal models"
            2 => "Collagen-induced arthritis"
            3 => "Transforming growth factor-beta"
            4 => "T cells"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec328514"
          "palabras" => array:5 [
            0 => "Artritis reumatoide"
            1 => "Modelos animales"
            2 => "Artritis-inducida con col&#225;geno"
            3 => "Factor de crecimiento transformador-beta"
            4 => "C&#233;lulas T"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">TGF-&#946; is a cytokine with pleiotropic functions in hematopoiesis&#44; angiogenesis&#44; cell proliferation&#44; differentiation&#44; migration and apoptosis&#46; Although its role in rheumatoid arthritis is not well defined&#44; TGF-&#946; activation leads to functional immunomodulatory effects according to environmental conditions&#46; The function of TGF-&#946; in the development of arthritis in murine models has been extensively studied with controversial results&#46; Recent findings point to a non-relevant role for TGF-&#946; in a mice model of collagen-induced arthritis&#46; The study of TGF-&#946; on T-cell responses has shown controversial results as an inhibitor or promoter of the inflammatory response&#46; This paper presents a review of the role of TGF-&#946; in animal models of arthritis&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El TGF-&#946; es una citocina implicada en procesos celulares como hematopoyesis&#44; proliferaci&#243;n&#44; angiog&#233;nesis&#44; diferenciaci&#243;n&#44; migraci&#243;n y apoptosis celular&#46; Aunque su papel en la artritis reumatoide no est&#225; bien definido&#44; est&#225; considerada como una citocina inmunomoduladora seg&#250;n las condiciones del entorno&#46; Numerosos trabajos han tratado de definir el papel del TGF-&#946; en el desarrollo de la artritis murina en diferentes modelos de enfermedad&#44; con resultados discordantes&#46; De hecho&#44; resultados recientemente publicados indican que TGF-&#946; no desempe&#241;a un papel relevante en el modelo murino de artritis inducida con col&#225;geno&#46; Su implicaci&#243;n en la diferenciaci&#243;n y la funcionalidad de las diferentes poblaciones de c&#233;lulas T tambi&#233;n ha mostrado resultados dispares sobre su papel como inhibidor o promotor de la respuesta inflamatoria&#46; En este trabajo se presenta una revisi&#243;n sobre el papel de TGF-&#946; en modelos animales de artritis&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gonzalo-Gil E&#44; Galindo-Izquierdo M&#46; Papel del factor de crecimiento transformador-beta &#40;TGF-&#946;&#41; en la fisiopatolog&#237;a de la artritis reumatoide&#46; Reumatol Clin&#46; 2014&#59;10&#58;174&#8211;179&#46;</p>"
      ]
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        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Role of TGF&#8211;&#946; in the differentiation of effector T cells&#46; Effect of TGF&#8211;&#946; and molecules involved in the differentiation and regulation of the different populations of effector T cells in relation to their role in the immune system&#46; IL&#44; interleukin&#59; TGF&#8211;&#946;&#44; transforming growth factor-beta&#59; Treg&#44; regulatory T cells&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Ab&#44; antibodies&#59; CAIA&#44; arthritis induced with anti-collagen antibodies&#59; CIA&#44; collagen-induced arthritis&#59; TGF&#8211;&#946; 1&#44; transforming growth factor-beta 1&#59; IP&#44; intraperitoneal&#59; SCW&#44; arthritis induced by <span class="elsevierStyleItalic">Streptococcus&#46;</span></p>"
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGF&#8211;&#946; 1 IP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#8211;28</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mice with CIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mesenchymal cells&#44; TGF&#8211;&#946; IP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mice with CIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-TGF&#8211;&#946; local and IP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Healthy mice and rats&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGF&#8211;&#946; 1 local&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rats with SCW&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-TGF&#8211;&#946; local&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mice with CAIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-TGF&#8211;&#946; RI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Role of TGF&#8211;&#946; in Animal Models of Arthritis&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:85 [
            0 => array:3 [
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                      "autores" => array:1 [
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                            1 => "U&#46; Muller-Ladner"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                      "Revista" => array:6 [
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            1 => array:3 [
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            3 => array:3 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                        0 => array:2 [
                          "etal" => true
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                            0 => "P&#46;V&#46; Kasperkovitz"
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                  ]
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                            1 => "S&#46; Takeshita"
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                            3 => "O&#46; Kanagawa"
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                  ]
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                            1 => "L&#46; van den Bersselaar"
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                  ]
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                            0 => "M&#46;M&#46; Shull"
                            1 => "I&#46; Ormsby"
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                      "Revista" => array:6 [
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Article information

ISSN: 21735743
Original language: English

DOI:10.1016/j.reumae.2014.01.006

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2023 October	118	43	161
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2023 July	95	33	128
2023 June	102	27	129
2023 May	100	36	136
2023 April	97	18	115
2023 March	124	46	170
2023 February	78	31	109
2023 January	109	22	131
2022 December	94	39	133
2022 November	103	38	141
2022 October	91	38	129
2022 September	95	51	146
2022 August	96	49	145
2022 July	80	50	130
2022 June	75	45	120
2022 May	131	52	183
2022 April	82	58	140
2022 March	104	54	158
2022 February	91	41	132
2022 January	122	53	175
2021 December	70	38	108
2021 November	64	60	124
2021 October	76	63	139
2021 September	68	68	136
2021 August	77	60	137
2021 July	185	55	240
2021 June	171	58	229
2021 May	200	39	239
2021 April	582	137	719
2021 March	453	65	518
2021 February	299	45	344
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2020 December	161	41	202
2020 November	134	28	162
2020 October	84	23	107
2020 September	126	55	181
2020 August	107	26	133
2020 July	68	23	91
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2020 May	43	19	62
2020 April	50	17	67
2020 March	59	13	72
2020 February	1	0	1
2018 May	9	0	9
2018 April	72	11	83
2018 March	107	19	126
2018 February	63	17	80
2018 January	69	12	81
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2017 November	95	13	108
2017 October	87	23	110
2017 September	89	13	102
2017 August	113	13	126
2017 July	83	16	99
2017 June	100	23	123
2017 May	128	27	155
2017 April	126	18	144
2017 March	119	40	159
2017 February	118	35	153
2017 January	111	16	127
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2016 August	228	25	253
2016 July	91	11	102
2016 April	3	0	3
2015 December	2	0	2
2015 September	2	0	2
2015 August	1	0	1
2015 July	65	10	75
2015 June	73	22	95
2015 May	94	18	112
2015 April	71	30	101
2015 March	65	16	81
2015 February	93	21	114
2015 January	93	21	114
2014 December	86	12	98
2014 November	89	23	112
2014 October	92	24	116
2014 September	96	19	115
2014 August	67	28	95
2014 July	93	29	122
2014 June	97	52	149
2014 May	65	34	99

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