EVect of interleukin 17 on proteoglycan degradation in murine knee joints

Objective—To evaluate the eVect of murine interleukin 17 (IL17) on cartilage catabolism and joint inflammation by direct intra-articular injection of the cytokine into murine knee joints. Methods—Knees of normal C57 Bl mice were injected once or repeatedly with recombinant IL17 or IL1â. Inflammation was estimated by technetium-99m pertechnetate (Tc) uptake and histological scoring of tissue sections. Proteoglycan depletion was evaluated by histological scoring of safranin O stained sections. EVects on proteoglycan synthesis were studied by 35SO4 incorporation. Results—A single intra-articular injection of IL17 (10 ng/knee) produced eVects very similar to those of IL1â (10 ng/knee). No inflammation was detected at six or 24 hours by Tc uptake. However, safranin O staining showed depletion of proteoglycan at 48 hours. Repeated injections of IL17 induced joint inflammation and cartilage proteoglycan depletion as shown by histological scoring. Unlike IL1â, proteoglycan depletion induced by IL17 seemed to be the result of increased degradation only, as no suppression of 35SO4 incorporation was seen. Conclusion—These findings confirm, in vivo, the catabolic eVects of IL17 on cartilage. IL17 is thus the first T cell cytokine showing a direct catabolic eVect on cartilage in addition to stimulatory eVects on macrophages and synoviocytes, making it a potentially important cytokine in the pathogenesis of arthritis. (Ann Rheum Dis 2000;59:529–532) Interleukin 17 (IL17), is a glycosylated homodimeric protein of 150 amino acids cloned from an activated T cell line, showing about 57% of homology to the open reading frame of a lymphotrophic virus, Herpesvirus saimiri. IL17 is secreted only by activated memory CD4+ T cells, 4 but its receptor is widely distributed, in particular in tissues of mesenchymal origin. 3 5 T cells have a critical role in rheumatoid pathogenesis. IL17 was found to be highly produced by rheumatoid, but not osteoarthritic, synovium. Furthermore, most of the T cells within rheumatoid synovium show a Th1 pattern of cytokine production. 8 Interestingly, only the Th1/Th0, but not Th2, subsets of CD4+ cell clones isolated from rheumatoid synovium produced IL17. In rheumatoid arthritis, T cells, macrophages, and mesenchymal cells all interact through autocrine, paracrine, and cell-contact pathways. IL17 may have an important role in this communication and interaction. It has been shown that IL17 can induce stromal cells to produce proinflammatory cytokines such as IL6, IL8, granulocyte colony stimulating factor, and prostaglandin E2. 10 IL17 induces IL6 and leukaemia inhibitory factor production by rheumatoid arthritis synoviocytes in a dose dependent manner, similarly to, but slightly less eYciently than, IL1â, and stimulates the production and expression of IL1â and tumour necrosis factor á by human macrophages. Other in vitro studies have also shown that IL17 could potentially initiate a matrix degradative response directly in cartilage through the up regulation of nitric oxide, stromelysin, or IL1â in chondrocytes. 14 Collectively, these observations suggest that IL17 may be an important factor in the initiation or maintenance of the T cell-dependent inflammation and cartilage matrix degradation in rheumatoid arthritis. The present in vivo study assessed the eVects of IL17 on cartilage catabolism after intra-articular injection of the cytokine. Materials and methods