Lipopolysaccharide- and gram-positive bacteria-induced cellular inflammatory responses:: role of heterotrimeric Gαi proteins

被引:38
作者
Fan, HK
Zingarelli, B
Peck, OM
Teti, G
Tempel, GE
Halushka, PV
Cook, JA
机构
[1] Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA
[2] Med Univ S Carolina, Dept Pharmacol, Charleston, SC 29425 USA
[3] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA
[4] Cincinnati Childrens Hosp, Med Ctr, Div Crit Care Med, Cincinnati, OH USA
[5] Med Univ Messina, Dept Expt Pathol & Microbiol, Messina, Italy
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2005年 / 289卷 / 02期
关键词
G(i) protein-deficient mice; endotoxin; group B streptococci; Staphylococcus aureus; Toll-like receptors;
D O I
10.1152/ajpcell.00394.2004
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Heterotrimeric G(i) proteins may play a role in lipopolysaccharide (LPS)-activated signaling through Toll-like receptor 4 (TLR4), leading to inflammatory mediator production. Although LPS is a TLR4 ligand, the gram-positive bacterium Staphylococcus aureus ( SA) is a TLR2 ligand, and group B streptococci (GBS) are neither TLR2 nor TLR4 ligands but are MyD88 dependent. We hypothesized that genetic deletion of Gi proteins would alter mediator production induced by LPS and gram-positive bacterial stimulation. We examined genetic deletion of G alpha(i2) or G alpha(i1/3) protein in G alpha(i2)-knockout (G alpha(i2) -/-) or G alpha i(1/3)-knockout (G alpha(i1/3) -/-) mice. LPS-, heat- killed SA-, or GBS-induced mediator production in splenocytes or peritoneal macrophages (M Phi) was investigated. There were significant increases in LPS-, SA-, and GBS-induced production of TNF-alpha and IFN-gamma in splenocytes from G alpha(i2) -/- mice compared with wild-type (WT) mice. Also, LPS-induced TNF-alpha was increased in splenocytes from G alpha(i1/3) -/- mice. In contrast to splenocytes, LPS-, SA-, and GBS-induced TNF-alpha, IL-10, and thromboxane B-2 (TxB(2)) production was decreased in M Phi harvested from G alpha(i2) -/- mice. Also, LPS- induced production of IL-10 and TxB2 was decreased in M Phi from G alpha(i1/3) -/- mice. In subsequent in vivo studies, TNF-alpha levels after LPS challenge were significantly greater in G alpha(i2) -/- mice than in WT mice. Also, myeloperoxidase activity, a marker of tissue neutrophil infiltration, was significantly increased in the gut and lung of LPS- treated G alpha(i2) -/- mice compared with WT mice. These data suggest that Gi proteins differentially regulate murine TLR-mediated inflammatory cytokine production in a cell-specific manner in response to both LPS and gram-positive microbial stimuli.
引用
收藏
页码:C293 / C301
页数:9
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