RRC ID 1970
Author Stoicov C, Cai X, Li H, Klucevsek K, Carlson J, Saffari R, Houghton J.
Title Major histocompatibility complex class II inhibits fas antigen-mediated gastric mucosal cell apoptosis through actin-dependent inhibition of receptor aggregation.
Journal Infect Immun
Abstract Escape from normal apoptotic controls is thought to be essential for the development of cancer. During Helicobacter pylori infection, the leading cause of gastric cancer, activation of the Fas antigen (Fas Ag) apoptotic pathway is responsible for early atrophy and tissue loss. As disease progresses, metaplastic and dysplastic glands arise which express Fas Ag but are resistant to apoptosis and are believed to be the precursor cells for adenocarcinoma. In this report, we show that one mechanism of acquired Fas resistance is inhibition of receptor aggregation via a major histocompatibility complex class II (MHCII)-mediated, actin-dependent mechanism. For these studies we used the well-described C57BL/6 mouse model of Helicobacter pylori and Helicobacter felis infection. Under normal conditions, Fas Ag is expressed at low levels, and MHCII expression on gastric mucosal cells is negligible. With infection and inflammation, both receptors are upregulated, and 6.1% of gastric mucosal cells express MHCII in combination with Fas Ag. Using the rat gastric mucosal cell line RGM-1 transfected with murine Fas Ag and MHCIIalphabeta chains, we demonstrate that MHCII prevents Fas receptor aggregation and inhibits Fas-mediated signaling through its effects on the actin cytoskeleton. Depolymerization of actin with cytochalasin D allows receptors to aggregate and restores Fas sensitivity. These findings offer one mechanism by which gastric mucosal cells acquire Fas resistance.
Volume 73(10)
Pages 6311-21
Published 2005-10-1
DOI 10.1128/IAI.73.10.6311-6321.2005
PII 73/10/6311
PMID 16177302
PMC PMC1230908
MeSH Actins / metabolism* Animals Apoptosis Cells, Cultured Cytochalasin D / pharmacology Gastric Mucosa / immunology* Gastric Mucosa / microbiology Gastric Mucosa / pathology Helicobacter Infections / immunology* Helicobacter Infections / metabolism Helicobacter Infections / pathology Helicobacter felis Helicobacter pylori Histocompatibility Antigens Class II / genetics Histocompatibility Antigens Class II / metabolism* Interferon-gamma / pharmacology Male Mice Mice, Inbred C57BL Rats Receptor Aggregation* / drug effects Signal Transduction fas Receptor / genetics fas Receptor / metabolism*
IF 3.201
Times Cited 13
Human and Animal Cells RGM1(RCB0876)