Lipoxin A(4) counteracts synergistic activation of human fibroblast-like synoviocytes

Excessive production of interleukin-6 (IL-6) and metalloproteinases (MMPs) has been implicated in the pathogenesis of rheumatoid arthritis. Lipoxin A(4) (LXA(4)) and transforming growth factor beta2 (TGF-beta2) have potential anti-inflammatory activities; these two mediators were tested to determine how they affect IL-1beta-dependent release of IL-6 and MMPs in human fibroblast-like synoviocytes. The results revealed dramatic differences between the mediators: TGF-beta2 acted synergistically with IL-1beta to stimulate IL-6 protein levels, whereas LXA(4) inhibited IL-6 expression in a dose- and time-dependent manner. Inhibition, by LXA(4) was abrogated when cells were pre-incubated with antibody against the ALXR (Lipoxin A., Receptor) TGF-beta2 by itself had no significant effect on IL-6 or NIMP levels. LXA(4), at nanomolar concentrations, altered the MMP-1 and MMP-3 expression levels of IL-1beta and TGF-beta2 stimulated fibroblast-like synoviocytes. Furthermore, IL-1beta and TGF-beta2 up-regulated ALXR mRNA. These results demonstrate, for the first time, that ALXR mediate the effects of LXA(4) on inflammatory responses after stimulation of fibroblast-like synoviocytes with IL-1beta plus TGF-beta2. These activities might constitute an important mechanism by which LXA(4) regulates synovial fibroblast activation.