Annexin-1 Mediates TNF-α-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-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.

Molecular regulators of resolution of inflammation: potential therapeutic targets in the reproductive system

“…LXA 4 inhibited IL1b-induced MMP3 synthesis in synovial fibroblasts with concurrent up-regulation of the counter-regulatory molecules tissue inhibitor of metalloproteinase-1 and -2 (Sodin-Semrl et al 2000). However, ANXA1 was shown to stimulate secretion of MMP1 in the same cell type suggesting that individual mediators might have functionally distinct roles in tissue remodelling (Tagoe et al 2008).…”

The emerging roles of ADAMTS-7 and ADAMTS-12 matrix metalloproteinases

“…[39][40][41][42][43] Real-time PCR analysis of cultured human cartilage explants show that both TNF and IL-1β strongly induce ADAMTS-7 and ADAMTS-12 expression. 44 Interestingly, this induction does not occur for ADAMTS-12 in human fetal fibroblasts, suggesting that there may be some tissue specificity for this effect.…”

Role of endogenous Annexin-A1 in the regulation of thymocyte positive and negative selection

“…30 Studies of the MAPK cascades activated during positive and negative selection have indicated that positively selected ligands induce a slow and sustained accumulation of Erk activity; in contrast, ligands that induce negative selection provoke a strong and transient burst of Erk phosphorylation. [31][32][33][34] Here we show that stimulation of AnxA1 -/-thymocytes with anti-CD3 caused a delayed and weaker phosphorylation of Erk1/2 compared to their NFκB than CD4 SP cells; and, furthermore, activation of this transcription factor determines the threshold of signalling responsible for positive and negative selection of MHC class I-restricted CD8 cells.…”