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

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-alpha. TNF-alpha induced a biphasic secretion of annexin-1 from RA SF. Early (< or = 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- (EC(50) approximately 25 microM) 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-alpha-stimulated MMP-1 secretion. Erk, Jnk, and NF-kappaB have been implicated in MMP-1 secretion. Erk, Jnk, and NF-kappaB inhibitors had no effect on annexin-1 secretion stimulated by TNF-alpha 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-alpha and acts in an autacoid manner to engage FPRL-1, activate Erk, Jnk, and NF-kappaB, and stimulate MMP-1 secretion.

• Authors: Clement E Tagoe, Nada Marjanovic, Jean Y Park, Edwin S Chan, Aryeh M Abeles, Mukundan Attur, Steven B Abramson, Michael H Pillinger
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 181 Issue 4 Pg. 2813-20 (Aug 15 2008) ISSN: 1550-6606 [Electronic] United States
• PMID: 18684973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Annexin A1
• FPR2 protein, human
• NF-kappa B
• Peptides
• Receptors, Formyl Peptide
• Receptors, Lipoxin
• Tumor Necrosis Factor-alpha
• annexin A1 peptide (2-26)
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 1

Topics

• Annexin A1 (metabolism, physiology)
• Arthritis, Rheumatoid (enzymology, immunology, pathology)
• Autocrine Communication (immunology)
• Cells, Cultured
• Extracellular Signal-Regulated MAP Kinases (metabolism, physiology)
• Fibroblasts (enzymology, immunology, pathology)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism, physiology)
• MAP Kinase Signaling System (immunology)
• Matrix Metalloproteinase 1 (biosynthesis, metabolism)
• NF-kappa B (metabolism, physiology)
• Peptides (metabolism, physiology)
• Receptors, Formyl Peptide (metabolism, physiology)
• Receptors, Lipoxin (metabolism, physiology)
• Synovial Membrane (enzymology, immunology, pathology)
• Tumor Necrosis Factor-alpha (physiology)