Lipoxin A4 inhibits IL-1β-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases

Snezna Sodin-Semrl, Brunella Taddeo, Daniel Tseng, John Varga, Stefano Fiore*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

183 Scopus citations

Abstract

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- 1β, in normal human synovial fibroblasts (SF). We examined whether exogenous LXA4 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, LXA4 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, 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.

Original languageEnglish (US)
Pages (from-to)2660-2666
Number of pages7
JournalJournal of Immunology
Volume164
Issue number5
DOIs
StatePublished - Mar 1 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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