RRC ID 42574
Author Hirata Y, Ohmae T, Shibata W, Maeda S, Ogura K, Yoshida H, Kawabe T, Omata M.
Title MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells.
Journal J Immunol
Abstract Helicobacter pylori induces NF-kappaB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-kappaB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-kappaB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-kappaB signaling intermediate molecules was evaluated in H. pylori-induced IkappaBalpha phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IkappaB kinase, TGF-beta-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-kappaB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IkappaBalpha phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-kappaB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.
Volume 176(6)
Pages 3796-803
Published 2006-3-15
DOI 10.4049/jimmunol.176.6.3796
PII 176/6/3796
PMID 16517750
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Animals Cells, Cultured Epithelial Cells / drug effects Epithelial Cells / metabolism* Epithelial Cells / microbiology* Genomic Islands Helicobacter pylori / immunology Helicobacter pylori / physiology* Humans Interleukin-8 / metabolism Lipopolysaccharides / pharmacology MAP Kinase Kinase Kinases / metabolism Mice Myeloid Differentiation Factor 88 NF-kappa B / metabolism Protein Binding Signal Transduction* TNF Receptor-Associated Factor 6 / metabolism*
IF 4.886
Times Cited 63
Human and Animal Cells HeLa(RCB0007) 293T(RCB2202)