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Corticosteroids Reduce IL-6 in ASM Cells via Up-Regulation of MKP-1

Respiratory Research Group, ¹ Faculty of Pharmacy and ² Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia

Correspondence and requests for reprints should be addressed to Alaina J. Ammit, Ph.D., Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia. E-mail: ajammit{at}pharm.usyd.edu.au

The mechanisms by which corticosteroids reduce airway inflammation are not completely understood. Traditionally, corticosteroids were thought to inhibit cytokines exclusively at the transcriptional level. Our recent evidence, obtained in airway smooth muscle (ASM), no longer supports this view. We have found that corticosteroids do not act at the transcriptional level to reduce TNF-–induced IL-6 gene expression. Rather, corticosteroids inhibit TNF-–induced IL-6 secretion by reducing the stability of the IL-6 mRNA transcript. TNF-–induced IL-6 mRNA decays at a significantly faster rate in ASM cells pretreated with the corticosteroid dexamethasone (t_1/2 = 2.4 h), compared to vehicle (t_1/2 = 9.0 h; P < 0.05) (results are expressed as decay constants [k] [mean ± SEM] and half-life [h]). Interestingly, the underlying mechanism of inhibition by corticosteroids is via the up-regulation of an endogenous mitogen-activated protein kinase (MAPK) inhibitor, MAPK phosphatase-1 (MKP-1). Corticosteroids rapidly up-regulate MKP-1 in a time-dependent manner (44.6 ± 10.5-fold increase after 24 h treatment with dexamethasone; P < 0.05), and MKP-1 up-regulation was temporally related to the inhibition of TNF-–induced p38 MAPK phosphorylation. Moreover, TNF- acts via a p38 MAPK-dependent pathway to stabilize the IL-6 mRNA transcript (TNF-, t_1/2 = 9.6 h; SB203580 + TNF-, t_1/2 = 1.5 h), exogenous expression of MKP-1 significantly inhibits TNF-–induced IL-6 secretion and MKP-1 siRNA reverses the inhibition of TNF-–induced IL-6 secretion by dexamethasone. Taken together, these results suggest that corticosteroid-induced MKP-1 contributes to the repression of IL-6 secretion in ASM cells.

Key Words: asthma • airway remodeling • chronic obstructive pulmonary disease

CLINICAL RELEVANCE In this study we investigate the molecular mechanisms by which corticosteroids suppress inflammation in airway smooth muscle, a pivotal immunomodulatory cell in asthma, in order to exploit these mechanisms in future therapies.

 

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