Production of interleukin (IL)-1 receptor antagonist by human articular chondrocytes

IL-1 receptor antagonist (IL-1Ra) is a member of the IL-1 family, which acts as a natural IL-1 inhibitor. The balance between IL-1 and IL-1Ra plays an important role in the course of various inflammatory diseases, such as arthritis. IL-1Ra is produced as different isoforms, one secreted (sIL-1Ra) and three intracellular (icIL-1Ra1, 2, 3), derived from the same gene. We examined the production of IL-1Ra isoforms by cultured human articular chondrocytes in response to various cytokines. The concentrations of IL-1Ra were measured by ELISA in conditioned media and cell lysates. The levels of IL-1Ra were undetectable in culture supernatants of untreated cells, but were significantly increased by IL-1β (IL-1). IL-1Ra secretion was first detectable after 24 hours and increased progressively thereafter, for at least 72 hours. In contrast, the cell lysates contained very low levels of IL-1Ra, even in response to IL-1 stimulation, suggesting that articular chondrocytes produce essentially the sIL-1Ra isoform. IL-6, which had no effect on its own, enhanced the effect of IL-1, while dexamethasone (dex) prevented the response. By RT-PCR, we observed that IL-1 and IL-6 induced mainly the production of sIL-1Ra mRNA. Furthermore, IL-1 alone or combined with IL-6 increased the levels of nascent unspliced sIL-1Ra mRNA, suggesting that sIL-1Ra expression is regulated at the transcriptional level. Consistently, reporter gene assays performed in immortalized human chondrocytes, C20/A4, showed increased sIL-1Ra promoter activity in response to IL-1 and IL-6. In conclusion, human articular chondrocytes produce sIL-1Ra in response to IL-1. This effect, which is enhanced by IL-6 and inhibited by dex, reflects increased transcription from the sIL-1Ra promoter. The production of sIL-1Ra by chondrocytes may have a protective effect against articular inflammatory and catabolic responses.