A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis
Åsa Betten, Johan Bylund, Thierry Cristophe, François Boulay, Ana Romero, Kristoffer Hellstrand, Claes Dahlgren
Åsa Betten, Johan Bylund, Thierry Cristophe, François Boulay, Ana Romero, Kristoffer Hellstrand, Claes Dahlgren
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Article

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

Abstract

Infection with Helicobacter pylori causes chronic gastritis, which is characterized by a dense mucosal infiltration by inflammatory cells such as monocytes/macrophages. H. pylori–induced inflammation is a risk factor for the development of gastric adenocarcinoma, but the mechanisms involved in H. pylori–associated carcinogenesis are poorly understood. A cecropin-like H. pylori peptide, Hp(2-20), was found to be a monocyte chemoattractant and activated the monocyte NADPH-oxidase to produce oxygen radicals. The receptors mediating monocyte activation were identified as FPRL1 and the monocyte-specific orphan receptor FPRL2. Hp(2-20)–activated monocytes inhibited lymphocytes with antitumor properties, such as CD56+ natural killer (NK) cells and CD3ε+ T cells. The changes observed in NK cells and T cells — a reduced antitumor cytotoxicity, downregulation of CD3ζ expression, and apoptosis — were mediated by Hp(2-20)–induced oxygen radicals. Histamine, a gastric mucosal constituent, rescued NK cells and T cells from inhibition and apoptosis by suppressing Hp(2-20)–induced oxygen radical formation. We conclude that H. pylori expression of this monocyte-activating peptide contributes to its ability to attract and activate monocytes and reduces the function and viability of antineoplastic lymphocytes. These novel mechanisms may be subject to local, histaminergic regulation in the gastric mucosa.

Authors

Åsa Betten, Johan Bylund, Thierry Cristophe, François Boulay, Ana Romero, Kristoffer Hellstrand, Claes Dahlgren

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Monocyte-dependent inhibition of NK cell cytotoxicity by Hp(2–20) (50 μM...
Monocyte-dependent inhibition of NK cell cytotoxicity by Hp(2–20) (50 μM), reversal by oxygen radical scavengers. NK cell–enriched lymphocytes (105 cells/well) were incubated with autologous monocytes for 16 hours at 37°C and assayed for cytotoxicity against 51Cr-labeled K562 cells (104 cells/well). (a) The cell cultures were treated with culture medium (control, open circles), Hp(2–20) (filled circles), or the control peptide Hp1 (50 μM) (filled boxes). Results are percentage of cell lysis (mean ± SEM of quadruplicates). Hp(2–20) did not significantly affect cytotoxicity in the absence of monocytes (not shown) but enhanced the monocyte-induced inhibition of cytotoxicity at all monocyte/lymphocyte ratios investigated (a). The monocyte-dependent inhibition of NK cell cytotoxicity by Hp(2–20) was confirmed in ten experiments using blood from different donors. In these experiments, the Hp(2–20)–induced inhibition was statistically significant over that induced by control monocytes at 37% monocytes (P < 0.005; Wilcoxon’s rank sum test) and 44% monocytes (P < 0.005). (b) The cell cultures were treated with Hp(2–20) (filled circles) or Hp(2–20) + SOD (50 U/ml) + catalase (200 U/ml) (filled boxes). Results are percentage of cell lysis (mean ± SEM results from eight experiments using blood from different donors). At all monocyte/lymphocyte ratios above 1:5 monocytes, SOD + catalase significantly rescued NK cell cytotoxicity from Hp(2–20)–induced inhibition (P < 0.01–0.001, Wilcoxon’s rank sum test for pairs).