A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis

Infection with Helicobacter pylori causes chronic gastritis, which is chara cterized by a dense mucosal infiltration by inflammatory cells such as mono cytes/macrophages. H. pylori-induced inflammation is a risk factor for the development of gastric adenocarcinoma, but the mechanisms involved in H. py lori-associated carcinogenesis are poorly understood. A cecropin-like H. py lori peptide, Hp(2-20), was found to be a monocyte chemoattractant and acti vated the monocyte NADPH-oxidase to produce oxygen radicals. The receptors mediating monocyte activation were identified as FPRL1 and the monocyte-spe cific orphan receptor FPRL2. Hp(2-20)-activated monocytes inhibited lymphoc ytes with antitumor properties, such as CD56(+) natural killer (NK) cells a nd CD3 epsilon T+ cells. The changes observed in NK cells and T cells - a r educed antitumor cytotoxicity, downregulation of CD3 zeta expression, and a poptosis - were mediated by Hp(2-20)-induced oxygen radicals. Histamine, a gastric mucosal constituent, rescued NK cells and T cells from inhibition a nd apoptosis by suppressing Hp(2-20)-induced oxygen radical formation. We c onclude that H. pylori expression of this monocyte-activating peptide contr ibutes to its ability to attract and activate monocytes and reduces the fun ction and viability of antineoplastic lymphocytes. These novel mechanisms m ay be subject to local, histaminergic regulation in the gastric mucosa.