Lipoxin A4 Counteracts Synergistic Activation of Human Fibroblast-like Synoviocytes

Abstract

Excessive production of interleukin-6 (IL-6) and metalloproteinases (MMPs) has been implicated in the pathogenesis of rheumatoid arthritis. Lipoxin A4 (LXA4) and transforming growth factor (32 (TGF-|32) have potential anti-inflammatory activities; these two mediators were tested to determine how they affect IL-1β-dependent release of IL-6 and MMPs in human fibroblast-like synoviocytes. The results revealed dramatic differences between the mediators: TGF-β2 acted synergistically with IL-1β to stimulate IL-6 protein levels, whereas LXA4 inhibited IL-6 expression in a dose- and time-dependent manner. Inhibition, by LXA4 was abrogated when cells were pre-incubated with antibody against the ALXR (Lipoxin A4 Receptor) TGF-β2 by itself had no significant effect on IL-6 or MMP levels. LXA4, at nanomolar concentrations, altered the MMP-1 and MMP-3 expression levels of IL-1β and TGF-β2 stimulated fibroblast-like synoviocytes. Furthermore, IL-1β and TGF-β2 up-regulated ALXR mRNA. These results demonstrate, for the first time, that ALXR mediate the effects of LXA4 on inflammatory responses after stimulation of fibroblast-like synoviocytes with IL-1β plus TGF-β2. These activities might constitute an important mechanism by which LXA4 regulates synovial fibroblast activation.