title: 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.affiliation: Division of Rheumatology, New York University School of Medicine/Hospital for Joint Diseases, New York, NY 10003, USA. ctagoe@montefiore.org
authors.forename: Clement E
authors.initials: CE
authors.lastname: Tagoe
authors.forename: Nada
authors.initials: N
authors.lastname: Marjanovic
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Park
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Chan
authors.forename: Aryeh M
authors.initials: AM
authors.lastname: Abeles
authors.forename: Mukundan
authors.initials: M
authors.lastname: Attur
authors.forename: Steven B
authors.initials: SB
authors.lastname: Abramson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Pillinger
mesh_terms: D017305:Annexin A1 / Q000378:metabolism / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019898:Autocrine Communication / Q000276:immunology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000276:immunology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D010455:Peptides / Q000378:metabolism / Q000502:physiology*; D044042:Receptors, Formyl Peptide / Q000378:metabolism / Q000502:physiology; D044067:Receptors, Lipoxin / Q000378:metabolism / Q000502:physiology; D013583:Synovial Membrane / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D017305:Annexin A1; C105101:FPR2 protein, human; D016328:NF-kappa B; D010455:Peptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha; C096153:annexin A1 peptide (2-26); D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1