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J. Biol. Chem., Vol. 280, Issue 25, 23451-23463, June 24, 2005

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Interleukin-1 Differentially Regulates ₂ Adrenoreceptor and Prostaglandin E₂-mediated cAMP Accumulation and Chloride Efflux from Calu-3 Bronchial Epithelial Cells

ROLE OF RECEPTOR CHANGES, ADENYLYL CYCLASE, CYCLO-OXYGENASE 2, AND PROTEIN KINASE A^*

Andrew Clayton, Elaine Holland, Linhua Pang, and Alan Knox

From the Division of Respiratory Medicine, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham NG5 1PB, United Kingdom

Here we tested the effect of interleukin-1, a pro-inflammatory cytokine, on cAMP accumulation and chloride efflux in Calu-3 airway epithelial cells in response to ligands binding to adenylyl cyclase-coupled receptors such as the ₂ adrenoreceptor and EP prostanoid receptors. Interleukin-1 significantly increased isoprenaline-induced cAMP accumulation by increasing ₂ adrenoreceptor numbers via a protein kinase A-dependent mechanism. In contrast, interleukin-1 significantly impaired prostaglandin E₂-induced cAMP accumulation by induction of cyclo-oxygenase-2, prostaglandin E₂ production, and a resulting down-regulation of adenylyl cyclase. The cAMP changes were all mirrored by alterations in chloride efflux assessed using the fluorescent chloride probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide with interleukin-1 increasing chloride efflux in response to isoprenaline and reducing the response to prostaglandin E₂. Studies with glibenclamide confirmed that chloride efflux was via the cystic fibrosis transmembrane conductance regulator. Calu-3 expresses EP₄ receptors, but not EP₂, and receptor expression is reduced by interleukin-1. Collectively, these results provide mechanistic insight into how interleukin-1 can differentially regulate cAMP generation and chloride efflux in response to different adenylyl cyclase-coupled ligands in the same cell. These findings have important implications for diseases involving inflammation and abnormal ion flux such as cystic fibrosis.

Received for publication, February 28, 2005

^* This work was supported by the Medical Research Council (UK). 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.

To whom correspondence should be addressed. Tel.: 44-115-8404775; Fax: 44-115-8404771; E-mail: alan.knox{at}nottingham.ac.uk.

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