Lipoxin A(4) inhibits IL-1 beta-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis oftissue 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)) do wn-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 LX A(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 n anomolar concentrations, LXA(4) inhibited these IL-1 beta responses with re duction of IL-6 and IL-8 synthesis, by 45 +/- 7% and 75 +/- 11%, respective ly, and prevented IL-1 beta-induced MMP-3 synthesis without significantly a ffecting MMP-1 levels. Furthermore, LXA(4) induced a 2-fold increase of tis sue inhibitor of metalloproteinase (TIMP)-1 and a similar to 3-fold increas e 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 mR NA 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.