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-1β, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA 4 abrogated IL-1β stimulation of SF in vitro. IL-1β induced the synthesis of IL-6, IL-8, and matrix metalloproteinases (MMP)-1 and-3. At nanomolar concentrations, LXA 4 inhibited these IL-1β responses with reduction of IL-6 and IL-8 synthesis, by 45±7% and 75±11%, respectively, and prevented IL-1β-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∼ 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.