Background/Purpose: Osteoarthritis (OA) is the most common joint disease, primarily characterized by progressive articular cartilage degradation. Cartilage destruction is assumed to be mediated by pro-inflammatory cytokines, including IL-1β, IL-6, IL-8 and TNFα  via induction of matrix degrading enzymes, such as matrix metalloproteinases (MMPs) and A Disintegrin-like and Metalloproteinases with Thrombospondin Motifs (ADAMTS). Recently, IL37 has come into view as an anti-inflammatory cytokine with inhibitory properties on innate immune responses by decreasing the production of pro-inflammatory cytokines. In this study we investigated  if IL37 is able to reduce the expression and secretion of pro-inflammatory cytokines and catabolic enzymes in human OA chondrocytes.

Methods: Cartilage was obtained from eight OA patients undergoing total knee or hip joint arthroplasty. First IL37 expression was analyzed by immunohistochemistry. To determine if IL37 expression is responsive to pro-inflammatory cytokines, chondrocytes were stimulated with IL-1β (10 ng/ml). IL37 gene expression was measured using qPCR. The functionality of IL37 was tested in primary human OA chondrocytes by overexpression of human IL37 via an adenovirus. Subsequently, chondrocytes were stimulated with IL-1β to create an OA-like environment. The effect of IL37 on the production and secretion of pro-inflammatory cytokines and enzymes in this environment was analyzed by qPCR, Western Blot and Luminex.

Results: In cartilage of OA patients, immunohistochemical analysis indicated that IL37 protein was indeed expressed by chondrocytes. Furthermore, we found that in primary OA chondrocytes the production of IL37 is significantly (p<0.0076) induced through IL-1β  stimulation. After overexpression, IL37 was effective to suppress IL-1β-induced gene expression of the pro-inflammatory cytokines IL-1β (p<0.0007), IL-6 (p<0.0043), IL-8 (p<0.0002) and the catabolic enzymes MMP3 (p<0.0010) and ADAMTS5 (p<0.0104) gene expression levels. In addition to gene expression analysis, we also studied the protein expression of pro-inflammatory cytokines in response to IL37 in primary OA chondrocytes. IL37 significantly reduced IL-1β-induced IL-6 (p<0.0111) and IL-8 protein (p<0.0001) levels in the supernatant of primary OA chondrocyte cultures. Furthermore, on Western blot analysis IL37 showed a reduction in IL-1β-induced IL-1β protein level.

Conclusion: In the present study, we showed basal IL37 protein expression and IL-1β- induced IL37 gene expression in human OA cartilage. This is the first study, demonstrating the enhanced expression of IL37 by primary human OA chondrocytes in an inflammatory environment. Furthermore, IL37 potently reduced the IL-1β-induced production and secretion of pro-inflammatory cytokines and catabolic enzymes. Clearly, these data implicate IL37 as a potent protective cytokine against cartilage degradation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il37-reduces-pro-inflammatory-cytokine-and-catabolic-enzyme-production-in-human-chondrocytes-a-protective-role-in-osteoarthritis/