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Section of Rheumatology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL 60607
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 A4 (LXA4) down-regulates inflammation
in vivo. Here we demonstrate, for the first time, the expression of
LXA4 receptors, and their up-regulation by IL-1ß, in
normal human synovial fibroblasts (SF). We examined whether exogenous
LXA4 abrogated IL-1ß stimulation of SF in vitro. IL-1ß
induced the synthesis of IL-6, IL-8, and matrix metalloproteinases
(MMP)-1 and -3. At nanomolar concentrations, LXA4 inhibited
these IL-1ß responses with reduction of IL-6 and IL-8 synthesis, by
45 ± 7% and 75 ± 11%, respectively, and prevented
IL-1ß-induced MMP-3 synthesis without significantly affecting MMP-1
levels. Furthermore, LXA4 induced a 2-fold increase of
tissue inhibitor of metalloproteinase (TIMP)-1 and a 
3-fold increase
of TIMP-2 protein levels. LXA4 inhibitory responses were
dose dependent and were abrogated by pretreatment with LXA4
receptor antiserum. LXA4-induced changes of IL-6 and TIMP
were accompanied by parallel changes in mRNA levels. These results
indicate that LXA4 in activated SF inhibits the synthesis
of inflammatory cytokines and MMP and stimulates TIMP production in
vitro. These findings suggest that LXA4 may be involved in
a negative feedback loop opposing inflammatory cytokine-induced
activation of SF.
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