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Regulation of the Adenosine Receptor (A2A) Expression: Differential Requirement for NF-
B Binding to the Proximal Promoter1
* Airways Disease Section, NHLI Imperial College London, London, United Kingdom; and
Department of Experimental Pharmacology, University of Naples "FedericoII," Naples, Italy
Adenosine is a potent endogenous regulator of airway inflammation that acts through specific receptor subtypes that can either cause constriction (A1R, A2BR, and A3R) or relaxation (A2AR) of the airways. We therefore examined the effects of key inflammatory mediators on the expression of the A2AR in a lung epithelial cell line (A549). IL-1β and TNF-
increased the expression of the A2AR gene at the mRNA and protein levels. In contrast, LPS had no effect on A2AR gene expression. IL-1β and TNF- rapidly activated p50 and p65, but not C-Rel, RelB, or p52, and both IL-1β- and TNF--stimulated A2AR expression was inhibited by the I
B kinase 2 inhibitor AS602868 in a concentration-dependent manner. Using chromatin immunoprecipitation assays, we demonstrate that IL-1β can enhance p65 association with putative B binding sites in the A2AR promoter in a temporal manner. In contrast, TNF- failed to enhance p65 binding to these putative sites. Functionally, the two most 5' B sites were important for IL-1β-, but not TNF--, induced A2AR promoter reporter gene activity. Finally, neither TNF- nor Il-1β had any effect on A2AR mRNA transcript degradation. These results directly implicate a major role for NF-B in the regulation of A2AR gene transcription by IL-1β and TNF- but suggest that the effects of TNF- on A2AR gene transcription are not mediated through the proximal promoter.
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 was funded by GlaxoSmithKline (U.K.).
2 Address correspondence and reprint requests to Dr. Ian M. Adcock, Airways Disease Section, Guy Scadding Building, National Heart & Lung Institute, Imperial College London, Dovehouse Street, London, SW3 6LY, U.K. E-mail address: ian.adcock{at}imperial.ac.uk
3 Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; IKK2, IB kinase; SLPI, secretory leukocyte protease inhibitor; ChIP, chromatin immunoprecipitation.
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