Interleukin‐22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts

Abstract

Objective. To examine the regulatory role of interleukin-22 (IL-22) in the expression of RANKL and induction of osteoclastogenesis in rheumatoid arthritis (RA).Methods. Concentrations of IL-22 and RANKL in the serum and synovial fluid of RA patients were measured using enzyme-linked immunosorbent assay. RA synovial fibroblasts were treated with recombinant human IL-22 (rhIL-22), and the expression of RANKL messenger RNA (mRNA) and protein was measured using real-time polymerase chain reaction, Western blotting, and intracellular immunostaining. Human monocytes were cocultured with IL-22-prestimulated RA synovial fibroblasts and macrophage colony-stimulating factor, and osteoclastogenesis was assessed by counting the multinucleated cells (those staining positive for tartrate-resistant acid phosphatase).Results. The IL-22 concentration in the synovial fluid was higher in RA patients than in patients with osteoarthritis (OA). The serum IL-22 concentration was also higher in RA patients than in OA patients and healthy volunteers, and this correlated with serum titers of rheumatoid factor and anti-cyclic citrullinated peptide antibodies. In RA synovial fibroblasts treated with rhIL-22, the expression of RANKL mRNA and protein was increased in a dose-dependent manner. IL-22-induced RANKL expression was down-regulated significantly by the inhibition of p38 MAPK/NF-B or JAK-2/STAT-3 signaling. In human monocytes cocultured with IL-22-prestimulated RA synovial fibroblasts in the absence of exogenous RANKL, the monocytes differentiated into osteoclasts, but this osteoclastogenesis decreased after p38 MAPK/NF-B or JAK-2/STAT-3 signaling was inhibited.Conclusion. These results show that IL-22 upregulates RANKL expression in RA synovial fibroblasts and induces osteoclastogenesis. These effects are mediated by the p38 MAPK/NF-B and JAK-2/STAT-3 signaling pathways.

Interleukin 22, a Potential Therapeutic Target for Rheumatoid Arthritis

“…The IL-22 concentration in synovial fluid was higher in patients with RA compared with controls 2,3 . In patients with RA, Th17 cells were recognized to produce higher IL-22 4 .…”

Immune Modulatory Effects of IL-22 On Allergen-Induced Pulmonary Inflammation

“…Besides its proinflammatory effects in autoimmune diseases and host defense, IL-17 can recruit neutrophils into the airways in allergic asthma [38]. After IL-22 was first described [39], extensive studies have shown that IL-22 has immunological effects, predominantly proinflammatory, in various diseases or models, such as bleomycin induced lung inflammation, and other disease models, including arthritis, hepatitis, psoriasis, atopic dermatitis, and inflammatory bowel disease [11,[40][41][42][43][44][45]. In the lung, IL-22 plays a key role in controlling bacteremia in experimental gram-negative pneumonia and airway tissue repair after influenza infection [22,25].…”

The Gut Microbiota and Inflammation in Rheumatoid Arthritis

“…IL-17 also increases the production of vascular endothelial growth factor (VEGF) in rheumatoid ibroblast-like synoviocytes (FLS), contributing to the angiogenesis in rheumatoid synovium. Finally, IL-17 stimulates the expression of various pro-inlammatory cytokines (e.g., IL-1β, TNF-α, and IL-6) and matrix-degrading enzymes (e.g., matrix metalloproteinase (MMP)-1, matrix metalloproteinase-2, matrix metalloproteinase-9, and matrix metalloproteinase-13) in whole synovial tissue, synovial ibroblasts, and cartilage, thus promoting inlammation, extracellular matrix breakdown, and cartilage destruction during RA development [61][62][63][64][65].…”