Suppression of PLCβ2 by Endotoxin Plays a Role in the Adenosine A2A Receptor-Mediated Switch of Macrophages from an Inflammatory to an Angiogenic Phenotype
Suppression of PLCβ2 by Endotoxin Plays a Role in the Adenosine A2A Receptor-Mediated Switch of Macrophages from an Inflammatory to an Angiogenic Phenotype
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DOI：
10.2353/ajpath.2009.090290
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发表时间：
2009-12-01
影响因子：
6
通讯作者：
Leibovich, Samuel Joseph
中科院分区：
文献类型：
--
作者：
Grinberg, Stan;Hasko, Gyorgy;Leibovich, Samuel Joseph
Toll样受体（TLR）2、4、7和9激动剂与腺苷A（2A）受体（A（2A）R）激动剂一起将巨噬细胞从炎性（M1）表型转变为血管生成（M2样）表型。这种转换涉及TLR激动剂诱导A（2A）Rs，下调肿瘤坏死因子α（TNF α）和白细胞介素-12，上调血管内皮生长因子（VEGF）和白细胞介素-10表达。我们在这里表明，TLR 4激动剂脂多糖（LPS）诱导快速和特异性的转录后下调磷脂酶C（PLC）β 1和β 2在巨噬细胞的表达;通过不稳定他们的mRNA。PLC β抑制剂U 73122下调巨噬细胞的TNF α表达，并且在A（2A）R激动剂存在下上调VEGF，模拟LPS与A（2A）R激动剂的协同作用。使用小干扰RNA选择性下调PLC β 2，而不是PLC β 1，导致对A（2A）R激动剂反应的VEGF表达增加，但不抑制TNF α表达。PLC β 2（-/-）小鼠的巨噬细胞对A（2A）R激动剂的反应也增加了VEGF的表达。LPS介导的PLC β 1和β 2的抑制是MyD 88依赖性的。在内毒素休克模型中，LPS（35 μ g/小鼠，i. p.）抑制野生型小鼠脾、肝和肺中PLC β 1和β 2的表达，但不抑制MyD 88（-/-）小鼠中PLC β 1和β 2的表达。这些研究表明，LPS抑制PLC β 1和β 2表达的巨噬细胞在体外和在体内的几个组织。这些结果表明，PLC 32的抑制在将M1巨噬细胞转换成M2样状态中起重要作用。(Am J Pathol 2009，175：2439-245 DOI：10.2353/ajpath.2009.090290）
Toll-like receptor (TLR) 2, 4, 7, and 9 agonists, together with adenosine A(2A) receptor (A(2A)R) agonists, switch macrophages; from an inflammatory (M1) to an angiogenic (M2-like) phenotype. This switch involves induction of A(2A)Rs by TLR agonists, down-regulation of tumor necrosis factor a (TNF alpha) and interleukin-12, and up-regulation of vascular endothelial growth factor (VEGF) and interleukin-10 expression. We show here that the TLR4 agonist lipopolysaccharide (LPS) induces rapid and specific post-transcriptional down-regulation of phospholipase C(PLC)beta 1 and beta 2 expression in macrophages; by destabilizing their mRNAs. The PLC beta inhibitor U73122 down-regulates TNF alpha expression by macrophages, and in the presence of A(2A)R agonists, up-regulates VEGF, mimicking the synergistic action of LPS with A(2A)R agonists. Selective down-regulation of PLC beta 2, but not PLC beta 1, using small-interfering RNA resulted in increased VEGF expression in response to A(2A)R agonists, but did not suppress TNF alpha expression. Macrophages from PLC beta 2(-/-) mice also expressed increased VEGF in response to A(2A)R agonists. LPS-mediated suppression of PLC beta 1 and beta 2 is MyD88-dependent. in a model of endotoxic shock, LPS (35 mu g/mouse, i.p.) suppressed PLC beta 1 and beta 2 expression in spleen, liver, and lung of wild-type but not MyD88(-/-) mice. These studies indicate that LPS suppresses PLC beta 1 and beta 2 expression in macrophages in vitro and in several tissues in vivo. These results suggest that suppression of PLC)32 plays an important role in switching M1 macrophages into an M2-like state. (Am J Pathol 2009, 175:2439-245 DOI: 10.2353/ajpath.2009.090290)