The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

被引:287
作者
Yang, Dan
Zhang, Ying
Nguyen, Hao G.
Koupenova, Milka
Chauhan, Anil K.
Makitalo, Maria
Jones, Matthew R.
Hilaire, Cynthia St.
Seldin, David C.
Toselli, Paul
Larnperti, Edward
Schreiber, Barbara M.
Gavras, Haralambos
Wagner, Denisa D.
Ravid, Katya
机构
[1] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA
[3] Harvard Univ, Sch Med, CBR, Inst Biomed Res, Boston, MA USA
[4] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[5] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA
关键词
D O I
10.1172/JCI27933
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Adenosine has been described as playing a role in the control of inflammation, but it has not been certain which of its receptors mediate this effect. Here, we generated an A(2B) adenosine receptor-knockout/reporter gene-knock-in (A(2B)AR-knockout/reporter gene-knock-in) mouse model and showed receptor gene expression in the vasculature and macrophages, the ablation of which causes low-grade inflammation compared with age-, sex-, and strain-matched control mice. Augmentation of proinflammatory cytokines, such as TNF-alpha, and a consequent downregulation of I kappa B-alpha are the underlying mechanisms for an observed upregulation of adhesion molecules in the vasculature of these A(2B)AR-null mice. Intriguingly, leukocyte adhesion to the vasculature is significantly increased in the A(2B)AR-knockout mice. Exposure to an endotoxin results in augmented proinflammatory cytokine levels in A(2B)AR-null mice compared with control mice. Bone marrow transplantations indicated that bone marrow (and to a lesser extent vascular) A(2B)ARs regulate these processes. Hence, we identify the A(2B)AR as a new critical regulator of inflammation and vascular adhesion primarily via signals from hematopoietic cells to the vasculature, focusing attention on the receptor as a therapeutic target.
引用
收藏
页码:1913 / 1923
页数:11
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