IL-6 and IL-1 synergistically enhanced the production of MMPs from synovial cells by up-regulating IL-6 production and IL-1 receptor I expression

In the present study, we investigated potential synergism between IL-6 and IL-1 for the production of matrix metalloproteinases (MMPs) by the synovial cell line SW982. Cells were cultured with different combinations of IL-6, soluble IL-6 receptor (sIL-6R) and IL-1β for 24 h and production of MMPs was then measured. IL-6 + sIL-6R, but not IL-6 alone, induced MMP-13 and MMP-3 production. IL-1β also induced production of MMPs. Of interest, addition of IL-6 + sIL-6R together with IL-1β synergistically increased MMP production. Next, we analyzed the mechanism responsible for the synergistic effects of IL-6 + sIL-6R and IL-1β in combination. IL-1β-induced MMP production was significantly augmented in the presence of sIL-6R. IL-1β as well as IL-6 + sIL-6R induced IL-6 production. Moreover, IL-6 + sIL-6R significantly augmented expression of IL-1RI, but not IL-1RII, in SW982 cells. Responsiveness to IL-1β was much higher in IL-6 + sIL-6R-pretreated cells than non-treated cells in terms of MMP production. Finally, IL-6 + sIL-6R-induced IL-1RI expression was inhibited by a STAT pathway inhibitor, but not a MAPK pathway inhibitor. These results suggest that increased expression of IL-1RI stimulated by IL-6 + sIL-6R and the increased production of IL-6 on exposure to IL-1β and IL-6 + sIL-6R are involved in the observed synergistic effect on the production of MMPs by SW982 cells.