EXTENDED REPORT

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

P J Koshy¹, N Henderson¹, C Logan¹, P F Life², T E Cawston¹ and A D Rowan¹

¹ Department of Rheumatology, School of Clinical Medical Sciences, The Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE4 2HH, UK
² Glaxo Wellcome R&D, Stevenage, UK

Correspondence to:
Correspondence to:
Dr A D Rowan, Department of Rheumatology, School of Clinical Medical Sciences, The Medical School, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne NE4 2HH, UK;
A.D.Rowan{at}ncl.ac.uk

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 (TNF), 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 ß1 (TGFß1) 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 TNF, 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, TGFß1, 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.

Keywords: cartilage; collagen; interleukin 17; synergy

Abbreviations: CNTF, ciliary neurotrophic factor; CT, cardiotrophin; GAGs, glycosaminoglycans; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; gp, glycoprotein; IGF, insulin-like growth factor; IL, interleukin; LIF, leukaemia inhibitory factor; LDH, lactate dehydrogenase; MMP, matrix metalloproteinase; OHPro, hydroxyproline; OSM, oncostatin M; RA, rheumatoid arthritis; TGF, transforming growth factor; TIMPs, tissue inhibitors of metalloproteinases; TNF, tumour necrosis factor

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