Major histocompatibility complex class II inhibits fas antigen-mediated gastric mucosal cell apoptosis through actin-dependent inhibition of receptor aggregation
Department of Medicine, Division of Gastroenterology
Medical Subject Headings
Actins; Animals; Antigens, CD95; Apoptosis; Cells, Cultured; Cytochalasin D; Gastric Mucosa; Helicobacter Infections; Helicobacter felis; Helicobacter pylori; Histocompatibility Antigens Class II; Interferon Type II; Male; Mice; Mice, Inbred C57BL; Rats; *Receptor Aggregation; Signal Transduction
Gastroenterology | Life Sciences | Medicine and Health Sciences
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.
Rights and Permissions
Citation: Infect Immun. 2005 Oct;73(10):6311-21. Link to article on publisher's site