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Annexin 1 Negatively Regulates IL-6 Expression via Effects on p38 MAPK and MAPK Phosphatase-1¹

Yuan H. Yang^*, Myew-Ling Toh^*, Colin D. Clyne, Michelle Leech^*, Daniel Aeberli^*, Jin Xue^*, April Dacumos^*, Laveena Sharma^* and Eric F. Morand^2,*

^* Centre for Inflammatory Diseases, Department of Medicine, Monash University, and Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by the National Health and Medical Research Council, Australia.

² Address correspondence and reprint requests to Prof. Eric F. Morand, Department of Medicine, Centre for Inflammatory Diseases, Monash University Monash Medical Centre, Locked Bag 29 Clayton, Victoria 3168, Australia. E-mail address: eric.morand{at}med.monash.edu.au

³ Abbreviations used in this paper: Anx-1, annexin 1; MKP-1, MAPK phosphatase-1; WT, wild type.

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