Annexin 1 negatively regulates IL-6 expression via effects on p38 MAPK and MAPK phosphatase-1.
Annexin 1 (Anx-1) is a mediator of the anti-inflammatory actions of glucocorticoids, but the mechanism of its anti-inflammatory effects is not known. We investigated the role of Anx-1 in the regulation of the proinflammatory cytokine, IL-6. Lung fibroblast cell lines derived from Anx-1(-/-) and wild-type (WT) mice were treated with dexamethasone and/or IL-1. IL-6 mRNA and protein were measured using real-time PCR and ELISA, and MAPK pathway activation was studied. Compared with WT cells, unstimulated Anx-1(-/-) cells exhibited dramatically increased basal IL-6 mRNA and protein expression. In concert with this result, Anx-1 deficiency was associated with increased basal phosphorylated p38, JNK, and ERK1/2 MAPKs. IL-1-inducible phosphorylated p38 was also increased in Anx-1(-/-) cells. The increase in IL-6 release in Anx-1(-/-) cells was inhibited by inhibition of p38 MAPK. Anx-1(-/-) cells were less sensitive to dexamethasone inhibition of IL-6 mRNA expression than WT cells, although inhibition by dexamethasone of IL-6 protein was similar. MAPK phosphatase-1 (MKP-1), a glucocorticoid-induced negative regulator of MAPK activation, was up-regulated by dexamethasone in WT cells, but this effect of dexamethasone was significantly impaired in Anx-1(-/-) cells. Treatment of Anx-1(-/-) cells with Anx-1 N-terminal peptide restored MKP-1 expression and inhibited p38 MAPK activity. These data demonstrate that Anx-1 is an endogenous inhibitory regulator of MAPK activation and IL-6 expression, and that Anx-1 is required for glucocorticoid up-regulation of MKP-1. Therapeutic manipulation of Anx-1 could provide glucocorticoid-mimicking effects in inflammatory disease.
Yang
Yuan H
YH
Centre for Inflammatory Diseases, Department of Medicine, Monash University Medical Centre, Clayton, Victoria 3168, Australia.
Toh
Myew-Ling
ML
Clyne
Colin D
CD
Leech
Michelle
M
Aeberli
Daniel
D
Xue
Jin
J
Dacumos
April
A
Sharma
Laveena
L
Morand
Eric F
EF
D000818:Animals; D017305:Annexin A1 / Q000276:immunology / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017305:Annexin A1; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D012333:RNA, Messenger; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases