Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)

被引:96
作者
Kostylina, G. [1 ]
Simon, D. [2 ]
Fey, M. F. [3 ]
Yousefi, S. [1 ]
Simon, H. U. [1 ]
机构
[1] Univ Bern, Dept Pharmacol, CH-3010 Bern, Switzerland
[2] Univ Bern, Dept Dermatol, CH-3010 Bern, Switzerland
[3] Univ Bern, Dept Med Oncol, CH-3010 Bern, Switzerland
关键词
apoptosis; Bad; cAMP; neutrophils; nicotinic acid;
D O I
10.1038/sj.cdd.4402238
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
G protein-coupled receptor (GPR) 109A (HM74A) is a G(i) protein-coupled receptor, which is activated by nicotinic acid (NA), a lipid-lowering drug. Here, we demonstrate that mature human neutrophils, but not eosinophils, express functional GPR109A receptors. The induction of the GPR109A gene appears to occur late in the terminal differentiation process of neutrophils, since a mixed population of immature bone marrow neutrophils did not demonstrate evidence for its expression. NA accelerated apoptosis in cultured neutrophils in a concentration-dependent manner, as assessed by phosphatidylserine redistribution, caspase-3 activation, and DNA fragmentation assays. The pro-apoptotic effect of NA was abolished by pertussis toxin, which was used to block Gi proteins, suggesting a receptor-mediated mechanism. Activation of GPR109A by NA resulted in decreased levels of cyclic adenosine monophosphate (cAMP), most likely due to G(i)-mediated inhibition of adenylyl cyclase activity. NA-induced apoptosis was reversed by the addition of cell-permeable cAMP, pointing to the possibility that reduced cAMP levels promote apoptosis in neutrophils. Distal mechanism involved in this process may include the post-translational modification of members of the Bcl-2 family, such as dephosphorylation of pro-apoptotic Bad and antiapoptotic Mcl-1 proteins. Taken together, following maturation in the bone marrow, neutrophils express functional GPR109A receptors, which might be involved in the regulation of neutrophil numbers. Moreover, this study identified a new cellular target of NA and future drugs activating GPR109A receptors, the mature neutrophil.
引用
收藏
页码:134 / 142
页数:9
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