期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 276, 期 44, 页码 40977-40981出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M105242200
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资金
- NCRR NIH HHS [M01RR00833] Funding Source: Medline
- NIAID NIH HHS [AI43524, T32 AI 07469] Funding Source: Medline
Chemoattractants bind to seven transmembrane-spanning, G-protein-coupled receptors on monocytes and neutrophils and induce a variety of functional responses, including activation of the transcription factor NF-kappaB. The signaling mechanisms utilized by chemoattractants to activate NF-kappaB in human peripheral blood monocytes are poorly defined. We previously demonstrated that fMet-Leu-Phe (fMLP) stimulates NF-kappaB activation, and this function of fMLP requires phosphatidylinositol 3-kinase (PI3K). Here we present evidence that fMLP activates RhoA and that fMLP-induced NF-kappaB activation requires this small GTPase. Stimulation of monocytes with fMLP rapidly activated RhoA as well as NF-kappaB, and their activation was markedly reduced by pertussis toxin treatment. Pretreatment of monocyte with a RhoA inhibitor, C3 transferase from Clostridium botulinum, effectively blocked fMLP-induced NF-kappaB activation as well as interleukin-1 beta gene expression. A dominant negative form of RhoA (T19N) also inhibited fMLP-stimulated reporter gene expression in a KB-dependent manner. Cotransfection of the monocytic THP1 cells with a constitutively active form of RhoA (Q63L) with the promoter reporter plasmid results in a marked increase in NF-kappaB-mediated reporter gene expression. Furthermore, the PI3K inhibitors wortmannin and LY294002 block RhoA activation induced by fMLP. These results demonstrate that low molecular weight GTPase RhoA is a novel signal transducer for fMLP-induced NF-kappaB activation and G alpha (i) or G alpha (o) class of heterotrimeric G proteins likely mediate RhoA activation via PI3K in human peripheral blood monocytes.
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