Suppression of PLCβ2 by endotoxin plays a role in the adenosine A 2A receptor-mediated switch of macrophages from an inflammatory to an angiogenic phenotype

Stan Grinberg, G. Haskó, Dianqing Wu, Samuel Joseph Leibovich

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Toll-like receptor (TLR) 2, 4, 7, and 9 agonists, together with adenosine A2A receptor (A2AR) agonists, switch macrophages from an inflammatory (M1) to an angiogenic (M2-like) phenotype. This switch involves induction of A2ARs by TLR agonists, down-regulation of tumor necrosis factor α (TNFα) 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 posttranscriptional down-regulation of phospholipase C(PLC)β1 and β2 expression in macrophages by destabilizing their mRNAs. The PLCβ inhibitor U73122 down-regulates TNFα expression by macrophages, and in the presence of A2AR agonists, up-regulates VEGF, mimicking the synergistic action of LPS with A2AR agonists. Selective down-regulation of PLCβ2, but not PLCβ1, using small-interfering RNA resulted in increased VEGF expression in response to A2AR agonists, but did not suppress TNFα expression. Macrophages from PLCβ2-/- mice also expressed increased VEGF in response to A2AR agonists. LPS-mediated suppression of PLCβ1 and β2 is MyD88-dependent. In a model of endotoxic shock, LPS (35 μg/mouse, i.p.) suppressed PLCβ1 and β2 expression in spleen, liver , and lung of wild-type but not MyD88-/- mice. These studies indicate that LPS suppresses PLCβ1 and β2 expression in macrophages in vitro and in several tissues in vivo. These results suggest that suppression of PLCβ2 plays an important role in switching M1 macrophages into an M2-like state.

Original languageEnglish
Pages (from-to)2439-2453
Number of pages15
JournalAmerican Journal of Pathology
Volume175
Issue number6
DOIs
Publication statusPublished - 2009

Fingerprint

Adenosine A2A Receptors
Endotoxins
Macrophages
Lipopolysaccharides
Phenotype
Vascular Endothelial Growth Factor A
Down-Regulation
Tumor Necrosis Factor-alpha
Type C Phospholipases
Up-Regulation
Adenosine A2 Receptor Agonists
Toll-Like Receptor 2
Toll-Like Receptor 4
Toll-Like Receptors
Interleukin-12
Septic Shock
Interleukin-10
Small Interfering RNA
Spleen
Lung

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medicine(all)

Cite this

Suppression of PLCβ2 by endotoxin plays a role in the adenosine A 2A receptor-mediated switch of macrophages from an inflammatory to an angiogenic phenotype. / Grinberg, Stan; Haskó, G.; Wu, Dianqing; Leibovich, Samuel Joseph.

In: American Journal of Pathology, Vol. 175, No. 6, 2009, p. 2439-2453.

Research output: Contribution to journalArticle

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