Activation of peroxisome proliferator-activated receptor gamma suppresses nuclear factor kappa B-mediated apoptosis induced by Helicobacter pylori ingastric epithelial cells

Helicobacter pylori colonization leads to epithelial cell hyperproliferatio n within inflamed mucosa, but levels of apoptosis vary, suggesting that imb alances between rates of cell production and loss may contribute to differe nces in gastric cancer risk among infected populations. Peroxisome prolifer ator-activated receptor gamma (PPAR gamma) regulates inflammatory and growt h responses of intestinal epithelial cells. We determined whether activatio n of PPAR gamma modified H. pylori-induced apoptosis in gastric epithelial cells. PPAR gamma was expressed and functionally active in gastric epitheli al cell lines sensitive to H. pylori-induced apoptosis. PPAR gamma ligands 15d-PGJ(2) and BRL-49653 significantly attenuated H. pylori-induced apoptos is, effects that could be reversed by co-treatment with a specific PPAR gam ma antagonist., Cyclopentanone prostaglandins that do not bind and activate PPAR gamma had no effects on H. pylori-induced apoptosis. The ability of H . pylori to activate nuclear factor (NF)-kappaB and increase levels of the NF-kappaB target IL-8 was blocked by co-treatment with PPAR gamma agonists, and direct inhibition of NF-kappaB also abolished H. pylori-stimulated apo ptosis. These results suggest that activation of the PPAR gamma pathway att enuates the ability of H. pylori to induce NF-kappaB-mediated apoptosis in gastric epithelial cells. Because PPAR gamma regulates a multitude of host responses, activation of this receptor may contribute to varying levels of cellular turnover as well as the diverse pathologic outcomes associated wit h chronic H. pylori colonization.