The role of the interleukin‐6 family of cytokines in inflammatory arthritis and bone turnover

Wong, Peter; Campbell, Ian K.; Egan, Paul J.; Ernst, Matthias; Wicks, Ian P.

doi:10.1002/art.10943

Cited by 128 publications

(86 citation statements)

References 159 publications

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“…Cytokines play a fundamental role in the processes that cause inflammation and articular destruction in RA (1). Besides tumor necrosis factor ␣ (TNF␣) and interleukin-1 (IL-1)-family cytokines, there is increasing evidence that IL-6 family members and signaling pathways downstream of the common gp130 receptor subunit are important in the pathogenesis of both murine and human inflammatory arthritis (2). Oncostatin M (OSM) is a member of the IL-6 family, and many studies have demonstrated that it has a stimulatory role in the progression of RA (3,4).…”

mentioning

confidence: 99%

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

Kok

Hou

Hong

et al. 2011

Arthritis & Rheumatism

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Objective. To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis.Methods. Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme-linked immunosorbent assay. In rats with collagen-induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination. Results. In primary human osteoblasts and U2OS

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mentioning

confidence: 99%

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

Kok

Hou

Hong

et al. 2011

Arthritis & Rheumatism

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“…IL-6 is a pleiotropic cytokine required for immune and inflammatory responses (7). IL-6 binds to its receptor (IL-6R␣), and the IL-6-IL-6R␣ complex induces gp130 homodimerization.…”

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confidence: 99%

Prostaglandin E2 Augments IL-10 Signaling and Function

Cheon

Rho

Choi

et al. 2006

The Journal of Immunology

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In inflamed joints of rheumatoid arthritis, PGE2 is highly expressed, and IL-10 and IL-6 are also abundant. PGE2 is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE2 on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE2 significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE2 suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE2-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE2-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE2 selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE2 may modulate immune responses by alteration of cytokine signaling in THP-1 cells.

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“…Third, IL-6, but not TNF␣, is a causative cytokine in ReA (Table 1, Figure 4, and Figures 5C and D). The efficacy of anti-IL-6 therapy in RA might be explained by the possible inhibition of disease exacerbation by activation of the TLR-4-mediated pathways (10,11,36). Thus, IL-6 might play an important role in the initiation and/or acceleration of inflammation in various types of arthritis, including ReA and RA.…”

Section: Discussionmentioning

confidence: 99%

“…Upon activation with IL-6, gp130, a signaling component of the IL-6 receptor (IL-6R), induces 2 distinct signals via activation of their different sites of tyrosine residues (11). Intriguingly, the absence of 1 of these 2 signaling pathways results in spontaneous development of arthritis, although the molecular bases for these 2 phenotypes is unknown (35).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of TLRs results in production of various proinflammatory cytokines, including arthritogenic tumor necrosis factor ␣ (TNF␣), interleukin-12 (IL-12), IL-18, interferon-␥ (IFN␥), and IL-6 (6)(7)(8)(9)(10)(11). Myeloid differentiation factor 88 (MyD88), a signal adaptor molecule, has been demonstrated to be essential for signaling via all of the TLRs except TLR-3 (12,13).…”

mentioning

confidence: 99%

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Endogenous interleukin‐6, but not tumor necrosis factor α, contributes to the development of toll‐like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice

Kyo¹,

Futani²,

Terada³

et al. 2005

Arthritis & Rheumatism

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Objective. To generate a mouse model of reactive arthritis (ReA), an aseptic synovitis that develops in joints distant from the primary bacterial infection site, to examine roles for Toll-like receptors (TLRs) that recognize bacterial components involved in the development of this arthritis, and to identify the cytokine(s) relevant to this arthritis.Methods. Mice were treated with cell wall extract from Escherichia coli (ECW) gram-negative bacterium by injection into the footpads. Seven days later, the mice were challenged with lipopolysaccharide (LPS), a TLR-4 ligand, which was injected into the knee joint cavity. To investigate the cytokine(s) involved in this arthritis, mice deficient in various arthritogenic cytokines, such as interleukin-6 (IL-6), IL-12, IL-18, interferon-␥, and tumor necrosis factor ␣ (TNF␣), were sequentially treated with ECW and LPS.Results. ECW-primed mice manifested acute severe arthritis after intraarticular challenge with ECW or LPS, while unprimed mice exhibited modest changes after these challenges. Mutant mice lacking functional TLR-4 or myeloid differentiation factor 88 (MyD88), an adaptor molecule of TLR-4 signaling, were resistant to this arthritis. Although both TNF␣ and IL-6 were equally expressed in the joint after LPS challenge, Il6 ؊/؊ mice, but not Tnf ؊/؊ mice, were resistant to ECW/LPS-induced arthritis.Conclusion. Our present results clearly indicate the importance of priming with ECW and the requirement of TLR-4/MyD88-mediated IL-6, but not TNF␣, for the development of ECW/LPS-induced arthritis. LPSinduced IL-6, in the absence of TNF␣, mediates LPSinduced arthritis. These results suggest that IL-6 is a rational target for therapeutic regimens for inflammatory arthritis, including ReA and rheumatoid arthritis.

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The role of the interleukin‐6 family of cytokines in inflammatory arthritis and bone turnover

Cited by 128 publications

References 159 publications

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

Prostaglandin E2 Augments IL-10 Signaling and Function

Endogenous interleukin‐6, but not tumor necrosis factor α, contributes to the development of toll‐like receptor 4/myeloid differentiation factor 88–mediated acute arthritis in mice

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