IL-1β and TNF-α regulation of the adenosine receptor (A 2A) expression: Differential requirement for NF-κB binding to the proximal promoter

Silvana Morello, Kazuhiro Ito, Satoshi Yamamura, Kang Yun Lee, Elen Jazrawi, Patricia DeSouza, Peter Barnes, Carla Cicala, Ian M. Adcock

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

Adenosine is a potent endogenous regulator of airway inflammation that acts through specific receptor subtypes that can either cause constriction (A 1R, A2BR, and A3R) or relaxation (A 2AR) 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-α 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-α rapidly activated p50 and p65, but not C-Rel, RelB, or p52, and both IL-1β- and TNF-α-stimulated A2AR expression was inhibited by the IκB kinase 2 inhibitor AS602868 in a concentration-dependent manner. Using chromatin immunoprecipitation assays, we demonstrate that IL-1β can enhance p65 association with putative κB binding sites in the A 2AR promoter in a temporal manner. In contrast, TNF-α failed to enhance p65 binding to these putative sites. Functionally, the two most 5′ κB sites were important for IL-1β-, but not TNF-α-, induced A2AR promoter reporter gene activity. Finally, neither TNF-α nor Il-1β had any effect on A2AR mRNA transcript degradation. These results directly implicate a major role for NF-κB in the regulation of A2AR gene transcription by IL-1β and TNF-α but suggest that the effects of TNF-α on A2AR gene transcription are not mediated through the proximal promoter.

Original languageEnglish
Pages (from-to)7173-7183
Number of pages11
JournalJournal of Immunology
Volume177
Issue number10
Publication statusPublished - Nov 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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