Chemoattractant-stimulated NF-kappa B activation is dependent on the low molecular weight GTPase RhoA

Citation
S. Huang et al., Chemoattractant-stimulated NF-kappa B activation is dependent on the low molecular weight GTPase RhoA, J BIOL CHEM, 276(44), 2001, pp. 40977-40981
Citations number
43
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
44
Year of publication
2001
Pages
40977 - 40981
Database
ISI
SICI code
0021-9258(20011102)276:44<40977:CNBAID>2.0.ZU;2-K
Abstract
Chemoattractants bind to seven transmembrane-spanning, G-protein-coupled re ceptors on monocytes and neutrophils and induce a variety of functional res ponses, including activation of the transcription factor NF-kappaB. The sig naling mechanisms utilized by chemoattractants to activate NF-kappaB in hum an peripheral blood monocytes are poorly defined. We previously demonstrate d that fMet-Leu-Phe (fMLP) stimulates NF-kappaB activation, and this functi on of fMLP requires phosphatidylinositol 3-kinase (PI3K). Here we present e vidence that fMLP activates RhoA and that fMLP-induced NF-kappaB activation requires this small GTPase. Stimulation of monocytes with fMLP rapidly act ivated RhoA as well as NF-kappaB, and their activation was markedly reduced by pertussis toxin treatment. Pretreatment of monocyte with a RhoA inhibit or, C3 transferase from Clostridium botulinum, effectively blocked fMLP-ind uced NF-kappaB activation as well as interleukin-1 beta gene expression. A dominant negative form of RhoA (T19N) also inhibited fMLP-stimulated report er gene expression in a KB-dependent manner. Cotransfection of the monocyti c THP1 cells with a constitutively active form of RhoA (Q63L) with the prom oter reporter plasmid results in a marked increase in NF-kappaB-mediated re porter gene expression. Furthermore, the PI3K inhibitors wortmannin and LY2 94002 block RhoA activation induced by fMLP. These results demonstrate that low molecular weight GTPase RhoA is a novel signal transducer for fMLP-ind uced NF-kappaB activation and G alpha (i) or G alpha (o) class of heterotri meric G proteins likely mediate RhoA activation via PI3K in human periphera l blood monocytes.