Chemoattractant-stimulated NF-κB Activation Is Dependent on the Low Molecular Weight GTPase RhoA

Shuang Huang, Ling Yu Chen, Bruce L. Zuraw, Richard D. Ye, Zhixing K. Pan

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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-κB. The signaling mechanisms utilized by chemoattractants to activate NF-κB in human peripheral blood monocytes are poorly defined. We previously demonstrated that fMet-Leu-Phe (fMLP) stimulates NF-κB activation, and this function of fMLP requires phosphatidylinositol 3-kinase (PI3K). Here we present evidence that fMLP activates RhoA and that fMLP-induced NF-κB activation requires this small GTPase. Stimulation of monocytes with fMLP rapidly activated RhoA as well as NF-κB, 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-κB activation as well as interleukin-1β gene expression. A dominant negative form of RhoA (T19N) also inhibited fMLP-stimulated reporter gene expression in a κB-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-κB-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-κB activation and Gαi of Gαo class of heterotrimeric G proteins likely mediate RhoA activation via PI3K in human peripheral blood monocytes.

Original languageEnglish (US)
Pages (from-to)40977-40981
Number of pages5
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - Nov 2 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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