Annexin-1 mediates TNF-α-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts

Clement E. Tagoe, Nada Marjanovic, Jean Y. Park, Edwin S. Chan, Aryeh M. Abeles, Mukundan Attur, Steven B. Abramson, Michael H. Pillinger

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40 Scopus citations

Abstract

Annexins are intracellular molecules implicated in the down-regulation of inflammation. Recently, annexin-1 has also been identified as a secreted molecule, suggesting it may have more complex effects on inflammation than previously appreciated. We studied the role of annexin-1 in mediating MMP-1 secretion from rheumatoid arthritis (RA) synovial fibroblasts (SF) stimulated with TNF-α. TNF-α induced a biphasic secretion of annexin-1 from RA SF. Early (≤60 min), cycloheximide-independent secretion from preformed intracellular pools was followed by late (24 h) cycloheximide-inhibitable secretion requiring new protein synthesis. Exogenous annexin-1 N-terminal peptide Ac2-26 stimulated MMP-1 secretion in a dose- (EC50 ≈ 25 μM) and time- (8-24 h) dependent manner; full-length annexin-1 had a similar effect. Down-regulation of annexin-1 using small interfering RNA resulted in decreased secretion of both annexin-1 and MMP-1, confirming that annexin-1 mediates TNF-α-stimulated MMP-1 secretion. Erk, Jnk, and NF-κB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-κB inhibitors had no effect on annexin-1 secretion stimulated by TNF-α but inhibited MMP-1 secretion in response to Ac2-26, indicating that these molecules signal downstream of annexin-1. Annexin-1 stimulation of MMP-1 secretion was inhibited by both a formyl peptide receptor antagonist and pertussis toxin, suggesting that secreted annexin-1 acts via formyl peptide family receptors, most likely FPLR-1. In contrast to its commonly appreciated anti-inflammatory roles, our data indicate that annexin-1 is secreted by RA SF in response to TNF-α and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-κB, and stimulate MMP-1 secretion.

Original languageEnglish (US)
Pages (from-to)2813-2820
Number of pages8
JournalJournal of Immunology
Volume181
Issue number4
StatePublished - Aug 15 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tagoe, C. E., Marjanovic, N., Park, J. Y., Chan, E. S., Abeles, A. M., Attur, M., Abramson, S. B., & Pillinger, M. H. (2008). Annexin-1 mediates TNF-α-stimulated matrix metalloproteinase secretion from rheumatoid arthritis synovial fibroblasts. Journal of Immunology, 181(4), 2813-2820.