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Published ahead of print on May 5, 2005, doi:10.1164/rccm.200409-1162OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 3, August 2005, 322-328

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Submitted on September 3, 2004
Accepted on April 29, 2005

Differential Desensitization of Homozygous Haplotypes of the {beta}2-Adrenergic Receptor in Lymphocytes

Jaap Oostendorp1, Dirkje S Postma2, Haukeline Volders1, Hajo Jongepier2, Henk F Kauffman3, H. Marike Boezen4, Deborah A Meyers5, Eugene R Bleecker5, S. Adriaan Nelemans1, Johan Zaagsma1, and Herman Meurs1*

1 Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands, 2 Department of Pulmonology, University of Groningen, Groningen, The Netherlands, 3 Department of Allergology, University of Groningen, Groningen, The Netherlands, 4 Department of Epidemiology, University of Groningen, Groningen, The Netherlands, 5 Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA

* To whom correspondence should be addressed. E-mail: h.meurs{at}rug.nl.

Single nucleotide polymorphisms of the {beta}2-adrenergic receptor gene and its 5' promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the {beta}2-adrenergic receptor (position 19 (Cys/Arg) of the 5' leader cistron and positions 16 (Arg/Gly) and 27 (Gln/Glu) of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well-defined non-asthmatic, non-allergic subjects homozygous for the haplotypes CysGlyGln, ArgGlyGlu or CysArgGln were isolated. Desensitization of (-)-isoproterenol-induced cAMP accumulation, {beta}2-adrenergic receptor sequestration and downregulation were measured in relation to {beta}2-adrenergic receptor-mediated inhibition of IFN{gamma} and IL-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the {beta}-agonist-induced cAMP response than ArgGlyGlu and CysArgGln, which was not associated with haplotype-dependent {beta}2-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition of {alpha}CD3/{alpha}CD28-induced IL-5 production in the CysGlyGln haplotype. This is the first study demonstrating haplotype-related differences in agonist-induced {beta}2-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the {beta}2-adrenergic receptor in lymphocytes might have consequences with regard to the regulation of Th2-type inflammatory responses.
Key words: single nucleotide polymorphism, 5' leader cistron, cAMP, sequestration and downregulation, cytokine production




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