Stimulation of 92-kd gelatinase (matrix metalloproteinase 9) production byinterleukin-17 in human monocyte/macrophages - A possible role in rheumatoid arthritis

Objective, To examine the cellular mechanisms by which the proinflammatory cytokine interleukin-17 (IL-17) induces the synthesis of 92-kd gelatinase ( matrix metalloproteinase 9 [MMP-9]) by human monocyte/macrophages in primar y culture. Methods, IL-17-stimulated human monocytes isolated from the peripheral bloo d of healthy donors were cultured in the presence of antiinflammatory cytok ines, neutralizing antibodies against IL-1 beta, tumor necrosis factor alph a (TNF alpha), or IL-1 receptor antagonist, and with protein kinase inhibit ors of diverse specificity. MMP measurements were performed using specific enzyme-linked immunosorbent assays, while the expression of specific messen ger RNA was determined by Northern blotting. Detection of phosphorylated pr oteins and specific transcriptional factors was performed by Western blotti ng and by gel retardation experiments, respectively. Results. Biologically active IL-17 was detected in the synovial fluid of pa tients with rheumatoid arthritis. IL-17-induced MMP-9 production in human m onocyte/macrophages was dependent on endogenous prostaglandin E-2 synthesis and related to autocrine stimulation by TNF alpha, but was IL-1 beta indep endent. This activation involves both p42/44 and p38 kinases and nuclear fa ctor kappa B. IL-17-inducible activator protein 1 and signal transducer and activator of transcription 1/3 may transactivate the MMP-9 promoter. Conclusion. IL-17 may contribute to an unbalanced production of proinflamma tory cytokines and MMP-9 in diseased articular joint tissues by interacting with the macrophages in the rheumatoid synovium.