Interleukin-18 Induces Rheumatoid Arthritis Synovial Fibroblast CXC Chemokine Production through NFκB Activation

Objective. Interleukin-18 (IL-18) is a proinflammatory cytokine implicated in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to examine the role of IL-18 in up-regulating secretion of the angiogenic factors stromal cell-derived factor 1␣ (SDF-1␣)/CXCL12, monocyte chemoattractant protein 1 (MCP-1)/CCL2, and vascular endothelial growth factor (VEGF) in RA synovial tissue (ST) fibroblasts, and the underlying signaling mechanisms involved.Methods. We used enzyme-linked immunosorbent assays, Western blotting, and chemical inhibitors/ antisense oligodeoxynucleotides to signaling intermediates to assess the role of IL-18.Results.

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confidence: 57%

“…All inhibitors were purchased from Calbiochem (San Diego, CA). Cells were pretreated for 1 hour with 10 M of each inhibitor before stimulation with IL-18 (25 nM), as described previously (25)(26)(27). TNF␣ (1.15 nM; Upjohn, Kalamazoo, MI) and phosphate buffered saline (PBS) were used as positive and negative controls, respectively.…”

Section: Methodsmentioning

confidence: 99%

Interleukin‐18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways

Amin

Mansfield

Pákozdi

et al. 2007

“…IL-18 is expressed in human RA synovium, and enhanced levels of IL-18 have been found in the sera of RA patients (19). Furthermore, IL-18 plays a role in the induction of RA synovial fibroblast expression of CXC chemokines through NF-B (20). IL-18 induces chondrocyte proliferation, up-regulates inducible nitric oxide synthase, stromelysin, IL-6, and cyclooxygenase 2 expression, and increases glycosaminoglycan release (15).…”

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confidence: 99%

Role of interleukin‐18 in experimental group B streptococcal arthritis

Tissi¹,

McRae²,

Ghayur³

et al. 2004

Objective. To assess the role of interleukin-18 (IL-18) in the evolution of septic arthritis induced by group B streptococci (GBS) in mice.Methods. CD1 mice were inoculated intravenously with 8 ؋ 10 6 colony-forming units (CFU) of type IV GBS (strain 1/82), and administered intraperitoneally 1 hour before infection with anti-IL-18 monoclonal antibodies (0.25 mg/mouse). In a subsequent set of experiments, mice infected with a suboptimal arthritogenic dose of GBS (4 ؋ 10 6 CFU/mouse) were administered different doses of recombinant IL-18 for 4 days, starting 1 hour after infection. Mortality, evolution of arthritis, bacterial clearance, joint histopathology, and cytokine production were examined in infected mice that did or did not receive treatment with anti-IL-18 antibodies or IL-18.Results. IL-18 was produced during GBS infection. Neutralization of IL-18 resulted in a decrease in mortality rates, and in the incidence and severity of arthritis. Amelioration of arthritis was accompanied by a dramatic reduction in local IL-1␤, IL-6, macrophage inflammatory protein 1␣ (MIP-1␣) and MIP-2 production, and reduced bacterial burden. Administration of exogenous IL-18 resulted in increased mortality rates and increased incidence and severity of GBS arthritis, concomitant with a higher number of GBS and increased levels of IL-6, IL-1␤, MIP-1␤, and MIP-2 production in the joints.Conclusion. The present study indicated some involvement of IL-18 in the pathogenesis of GBSinduced arthritis. The role of IL-18 in joint pathology is shown by a regulatory effect on inflammatory mediator levels and local cell influx. Thus, IL-18 should be regarded as a potential therapeutic target in GBS infection and arthritis.

“…FLS are a major source of chemokines in rheumatoid synovium, particularly when activated (10,34,35). The activation of FLS can be mediated by cytokines derived from monocyte/macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…In the RA joint, chemokines can be released by various cell types. The fibroblasts in the synovial lining layer, together with the macrophages, are a major source of chemokines, particularly when stimulated with proinflammatory cytokines (10).…”

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confidence: 99%

Augmented production of chemokines by the interaction of type II collagen–reactive T cells with rheumatoid synovial fibroblasts

Min¹,

Cho²,

Lee³

et al. 2004