Combination of IL-1β and IL-17A synergistically induce an early inflammatory and degenerative expression profile in healthy chondrocytes and synovial fibroblasts


Hart, Melanie (G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Dept. Orthopedics and Trauma Surgery, University of Freiburg Medical Center )


"Introduction: IL-1β and IL-17 are highly present in the synovial fluid after joint trauma and are plausible factors in the development of post-traumatic osteoarthritis (PTOA). Although a growing number of studies have identified a role for IL-17 in OA, the mechanisms underlining the pathophysiological role of IL-17A in early PTOA disease in healthy joint cells remains unclear. We performed a side-by-side study comparing the effects of IL-1β, IL-17A and their combination in synovial fibroblast (SFs) vs. chondrocyte (CHs) in vitro cultures to understand the contributing role of each of these cells in mediating early inflammatory and degenerative effects in healthy cells of the joint.

Methodology: Healthy bovine CHs (passage 1 [P1]) and SFs (P1 containing macrophages and P5 consisting only of SFs) were stimulated with IL-1β, IL-17A and their combination for 3 days to mimic acute inflammation, then cultured in medium without or with cytokines for 3 additional days to understand the post-acute (PA) vs. persistent/chronic (C) inflammatory response, respectively. Absolute quantification of gene expression was performed by ddPCR at d3, d6(PA) and d6(C) for stimulated as well as unstimulated cells (CN).

Results: In healthy CHs and SF(P1) and SF(P5), IL-1β+IL-17A synergistically and significantly decreased COL2A1 (CHs) and increased IL-6 and IL-8 in almost all cell types after acute (d3) and persistent [d6(C)] inflammation. Three days after cytokine withdrawal, IL-17A led to post-acute gene modifying effects in all cell types and significantly increased IL-6 [in CHs, SFs(P1,P5)] and IL-8 [in SFs(P1,P5)] vs. CN, suggesting post-acute contributing effects of IL-17A in inducing inflammation within the joint. SF(P1) > SF(P5) ≥ CHs cultures expressed the highest levels of IL-6 (d3), IL-8 (d3 and d6C), and MMP-2 [(d3, d6(PA), d6(C)] in response to all cytokines, which may be due to the presence of macrophage-like synoviocytes. In response to all cytokine treatments and in all conditions tested [d3, d6(PA), d6(C)], MMP-3 expression tended to equally increase in CHs vs. CN. Moreover, MMP-2 expression significantly increased in response to IL-1β, IL-17A and their combination vs. CN [d6(C)] in CHs.

Conclusion: IL-17A and IL-1β synergistically induce an early inflammatory and degenerative expression profile in healthy CHs and SFs. While both cell types (CHs and SFs) contribute to the early events following treatment, IL-1β and IL-17A treated healthy SFs [(SF(P1)>SF(P5)] contribute more than CHs in upregulating the expression of inflammatory cytokines and the cartilage matrix-degrading enzyme MMP-2, which can participate in the degradation of a wide range of ECM proteins found in cartilage tissue and may be due to presence of macrophage-like synoviocytes. This suggests that the combination of IL-17A and IL-1β synergistically induce early inflammatory and degenerative effects which could drive a chronic feedback loop of inflammation and degradation of cartilage tissue that involves cross-talk and feedback among chondrocytes, synovial fibroblasts and macrophage-like synoviocytes and thereby promote PTOA progression."


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