Lipoxin A4 inhibits IL-1β-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases

Lipoxins are a novel class of endogenous eicosanoid mediators that potently inhibit inflammatory events by signaling via specific receptors expressed on phagocytic cells. Animal models have shown that lipoxin A(4) (LXA(4)) down-regulates inflammation in vivo. Here we demonstrate, for the first time, the expression of LXA(4) receptors, and their up-regulation by IL-1 beta, in normal human synovial fibroblasts (SF), We examined whether exogenous LXA(4) abrogated IL-1 beta stimulation of SF in vitro, IL-1 beta induced the synthesis of IL-6, IL-8, and matrix metalloproteinases (MMP)-1 and -3, At nanomolar concentrations, LXA(4) inhibited these IL-1 beta responses with reduction of IL-6 and IL-8 synthesis, by 45 +/- 7% and 75 +/- 11%, respectively, and prevented IL-1 beta-induced MMP-3 synthesis without significantly affecting MMP-1 levels. Furthermore, LXA(4) induced a 2-fold increase of tissue inhibitor of metalloproteinase (TIMP)-1 and a similar to 3-fold increase of TIMP-2 protein levels. LXA(4) inhibitory responses were dose dependent and were abrogated by pretreatment with LXA(4) receptor antiserum. LXA(4)-induced changes of IL-6 and TIMP were accompanied by parallel changes in mRNA levels. These results indicate that LXA(4) in activated SF inhibits the synthesis of inflammatory cytokines and MMP and stimulates TIMP production in vitro, These findings suggest that LXA(4) may be involved in a negative feedback loop opposing inflammatory cytokine-induced activation of SF.