Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines

Abstract

Objective: To investigate whether interleukin 17 (IL17), derived specifically from T cells, can promote type II collagen release from cartilage. The ability of IL17 to synergise with other proinflammatory mediators to induce collagen release from cartilage, and what effect anti-inflammatory agents had on this process, was also assessed. Methods: IL17 alone, or in combination with IL1, IL6, oncostatin M (OSM), or tumour necrosis factor α (TNFα), was added to bovine nasal cartilage explant cultures. Proteoglycan and collagen release were determined. Collagenolytic activity was determined by bioassay. Chondroprotective effects of IL4, IL13, transforming growth factor β1 (TGFβ1) and insulin-like growth factor-1 (IGF1) were assessed by inclusion in the explant cultures. Results: IL17 alone stimulated a dose dependent release of proteoglycan and type II collagen from bovine nasal cartilage explants. Suboptimal doses of IL17 synergised potently with TNFα, IL1, OSM, and IL6 to promote collagen degradation. This collagen release was completely inhibited by tissue inhibitor of metalloproteinase-1 and BB-94 (a synthetic metalloproteinase inhibitor), and was significantly reduced by IL4, IL13, TGFβ1, and IGF1. In IL17 treated chondrocytes, mRNA expression for matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 was detected. Moreover, a synergistic induction of these MMPs was seen when IL17 was combined with other proinflammatory cytokines. Conclusions: IL17 can, alone and synergistically in combination with other proinflammatory cytokines, promote chondrocyte mediated MMP dependent type II collagen release from cartilage. Because levels of all these proinflammatory cytokines are raised in rheumatoid synovial fluids, this study suggests that IL17 may act as a potent upstream mediator of cartilage collagen breakdown in inflammatory joint diseases.

Induction of cartilage damage by overexpression of T cell interleukin‐17A in experimental arthritis in mice deficient in interleukin‐1

“…IL-17 increases the spontaneous production of MMP-1 by synoviocytes (36) and induces MMP-9 production in human monocyte/macrophages (15). In IL-17-treated chondrocytes, expression of mRNA for MMPs 1, 3, and 13 was detected, and a synergistic induction of these MMPs was seen when IL-17 was combined with other proinflammatory cytokines (14). Stimulation of normal human articular chondrocytes with IL-17 was shown to induce nitric oxide production and increase iNOS expression (37).…”

“…In vitro studies have shown that IL-17, acting in synergy with IL-1 or TNF, has powerful effects on cytokine (9,27,28) and chemokine (8) induction and cartilage degradation (14,29). The aggravation of arthri- tis by IL-17 during the first days of SCW-induced arthritis could be caused by additional, or even synergistic, effects of IL-17 in the presence of IL-1 and TNF, both of which are abundantly produced just after the onset of SCW-induced arthritis (30,31).…”

Treatment with a neutralizing anti‐murine interleukin‐17 antibody after the onset of collagen‐induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion

“…In vitro, it inhibits chondrocyte metabolism in intact articular cartilage of mice and results in proteoglycan breakdown (19,20,30,31). Furthermore, in vitro studies show the induction of metalloproteinases by IL-17 in synoviocytes and chondrocytes (32)(33)(34). Interestingly, the effects of IL-17 on matrix degradation and synthesis were not dependent on IL-1␤ production by chondrocytes, and IL-1 receptor antagonist did not block IL-17-induced matrix release nor did it prevent the inhibition of matrix synthesis in vitro using porcine articular cartilage explants (31).…”

Blocking of Interleukin-17 during Reactivation of Experimental Arthritis Prevents Joint Inflammation and Bone Erosion by Decreasing RANKL and Interleukin-1

“…cess by which joint inflammation is suppressed. Previous in vitro and ex vivo studies have shown the great capacity of IL-17 to synergize with TNF-␣ and IL-1 in the induction of other cytokines and chemokines 31,32 and the degradation of cartilage 33,34 and bone. 35 The interaction of IL-17 with other cytokines during reactivation of experimental arthritis, in particular the additive and synergistic effects with TNF-␣ and IL-1, might play an important role in preventing joint pathology.…”