Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis

Kehlen, Astrid; Thiele, Kathi; Riemann, Dagmar; Langner, Jürgen

doi:10.1046/j.1365-2249.2002.01782.x

Cited by 103 publications

(94 citation statements)

References 40 publications

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“…The inhibitory effect of genistein on IL-17-induced IL-8 had already been observed in synovial fibroblasts. 26 Consequently, genistein has been suggested as a substance that has antiinflammatory potential in the treatment of rheumatic diseases. 26,27 However, although genistein downregulates TNF-a inflammatory effects, it still cannot induce adipogenesis in the presence of TNF-a.…”

Section: Discussionmentioning

confidence: 99%

“…26 Consequently, genistein has been suggested as a substance that has antiinflammatory potential in the treatment of rheumatic diseases. 26,27 However, although genistein downregulates TNF-a inflammatory effects, it still cannot induce adipogenesis in the presence of TNF-a. These results suggest that TNF-ainduced inflammatory and anti-adipogenic pathways are at least partially distinct.…”

Section: Discussionmentioning

confidence: 99%

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Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Relić

Zeddou

Desoroux

et al. 2009

Laboratory Investigation

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It was shown recently that synovial fibroblast transformation into adipocytes reduced the expression of interleukin-6 (IL-6) and IL-8. However, the synovial fibroblast adipogenesis was inhibited in inflammatory conditions induced by the tumor necrosis factor-a (TNF-a). Furthermore, adipogenesis is often accompanied by leptin production, a proinflammatory adipokine in rheumatic diseases. In this study, we tested the phytohormone genistein for adipogenic and anti-inflammatory properties on human synovial fibroblasts. Results showed that genistein was able to transform synovial fibroblasts into adipocytes that expressed perilipin-A and produced adiponectin, but not leptin. Furthermore, genistein enhanced glucocorticoid-mediated synovial fibroblast adipogenesis and, in parallel, downregulated glucocorticoid-induced leptin and leptin receptor. Endogenous and TNF-a-induced expressions of IL-6, IL-8, p38, p65 and C/EBP-b were also downregulated by genistein, showing its anti-inflammatory properties. Peroxisome proliferatoractivated receptor-g (PPAR-g) agonist, rosiglitazone, had a synergic effect on genistein-induced adipogenesis, whereas the non-active tyrosine kinase inhibitor, daidzein, had a significantly inferior adipogenic activity than genistein. The Janus kinase-2 tyrosine kinase inhibitor, AG 490, mimicked the anti-leptin effect of genistein. These results showed that genistein-induced adipogenesis involves PPAR-g induction and tyrosine kinase inhibition. In conclusion, genistein, alone or coupled with glucocorticoids, have both adipogenic and anti-inflammatory effects on synovial fibroblasts.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Relić

Zeddou

Desoroux

et al. 2009

Laboratory Investigation

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“…The site where Th1 and/or Th17 cells were induced to differentiate and expand into pathogenic effector cells in rheumatoid arthritis is not known yet, but the fact that at the preclinical stage of AIA the CD4+/CD8+ T cell ratio is shifted toward the CD4+ subset systemically (blood and spleen) but not locally (within draining inguinal and popliteal LNs) permits the speculation that Th17 T cells are transformed into pathogenic effectors systemically and then circulate widely, including regular forays into the sites of local inflammation (i.e., joints). Furthermore, a synergistic effect among IL-17, IL-1, TGFβ, and TNFα could drive differentiation, maturation, activation, and cytokine release by neutrophils, monocytes, and synovial fibroblasts [60,62,63], thereby leading eventually to the visible onset of clinical arthritis in RA patients and experimental animals.…”

Section: Discussionmentioning

confidence: 99%

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

et al. 2008

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Introduction Rats with adjuvant-induced arthritis (AIA) were necropsied on 14 occasions during preclinical, acute clinical and chronic clinical stages of AIA progression to characterize local (joint protein extracts) and systemic (serum) levels of mediators regulating inflammation and bone erosion in conjunction with lymphoid tissue-specific leukocyte kinetics. Results Systemic increases in alpha1 acid glycoprotein, tumor necrosis factor-α (TNFα), interleukin (IL)-17, transforming growth factor beta (TGFβ), and chemokine (C-C motif) ligand 2 (CCL2) together with local IL-1α/β and TGFβ enrichment and local lymphoid hyperplasia preceded the onset of clinical disease and joint damage. Systemic upregulation of TNFα, IL-6, IL-17, TGFβ, IL-18, CCL2, receptor activator of nuclear factor-κβ ligand (RANKL), and prostaglandin E 2 during acute and/or chronic AIA coincided with systemic leukocytosis and CD4+ T cell increase in blood and spleen. In contrast, progression of joint erosions during clinical AIA was associated with intraarticular increases in IL-1α/β, IL-6, RANKL, IL-17, TGFβ, CCL2, and KC/GRO and also a dramatic decline in osteoprotegerin. Conclusion These data indicate that systemic and local events in inflammatory arthritis are discrete processes, driven by multiple cellular and humoral mediators with distinct kinetic profiles.

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“…IL-17F was reported to employ IL-17R for signaling and IL-17F and IL-17A could induce IL-17R ubiquitination and DN-TRAF6, a dominant-negative mutant, could block IL-17F but not IL-17A triggered ubiquitination of IL-17R [46]. The IL-17R is ubiquitously expressed in virtually all cells and tissue and its expression was shown on synoviocytes, chondrocytes and synovial endothelial cells [47][48][49]. Expression of different IL-17 homologs (IL-17A, C, E and F) was detected in synovial fluid mononuclear cells from RA patients and different IL-17R (IL-17RA, IL-17RB, C and D) expression was noted in fibroblast-like synoviocytes of RA patients [50].…”

Section: What Is the Most Physiologically Relevant Target Of Il-17a Imentioning

confidence: 99%

IL-17/Th17 targeting: On the road to prevent chronic destructive arthritis?

Lubberts¹

2008

Cytokine

270

230

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Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis. Data from experimental arthritis indicate IL-17 receptor signaling as a critical pathway in turning an acute synovitis into a chronic destructive arthritis. The identification of six IL-17 family members (IL-17A-F) may extend the role of this novel cytokine family in the pathogenesis of chronic destructive joint inflammation. Whether the successful anti-IL-17A cytokine therapy in murine arthritis can be effectively translated to human arthritis need to be tested in clinical trials in humans. Interestingly, IL-17A and IL-17F are secreted by the novel T helper subset named Th17. This novel pathogenic T cell population induces autoimmune inflammation in mice and is far more efficient at inducing Th1-mediated autoimmune inflammation in mice than classical Th1 cells (IFN-c). In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26. Th17 cells have been established as a separate lineage of T helper cells in mice distinct from conventional Th1 and Th2 cells. Whether this also applies to human Th17 and whether RA is a Th1 or a Th17 mediated disease is still not clear. This review summarizes the findings about the role of IL-17 in arthritis and discusses the impact of the discovery of the novel Th17 cells for arthritis. Further studies are needed to unravel the role of Th17 cells and the interplay of IL-17 and other Th17 cytokines in the pathogenesis of arthritis and whether regulating Th17 cell activity will have additional value compared to neutralizing IL-17A activity alone. This might help to reach the ultimate goal not only to treat RA patients but to prevent the development of this crippling disease.

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Expression, modulation and signalling of IL-17 receptor in fibroblast-like synoviocytes of patients with rheumatoid arthritis

Cited by 103 publications

References 40 publications

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

Genistein induces adipogenesis but inhibits leptin induction in human synovial fibroblasts

The Evolving Systemic and Local Biomarker Milieu at Different Stages of Disease Progression in Rat Adjuvant-Induced Arthritis

IL-17/Th17 targeting: On the road to prevent chronic destructive arthritis?

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