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

• 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 CD3epsilon+ T cells. The changes observed in NK cells and T cells--a reduced antitumor cytotoxicity, downregulation of CD3zeta 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.

Keyword

Adenocarcinoma/etiology

Amino Acid Sequence

Apoptosis

Bacterial Proteins/chemistry/*immunology/pharmacology

Chemotaxis

Leukocyte

Gastritis/etiology

Helicobacter Infections/etiology

Helicobacter pylori/*immunology/*pathogenicity

Humans

Inflammation Mediators/chemistry/immunology/pharmacology

Lymphocytes/cytology/immunology

Molecular Sequence Data

Monocytes/*immunology

NADPH Oxidase/metabolism

Peptides/chemistry/*immunology/pharmacology

Receptors

Formyl Peptide

Receptors

Immunologic/immunology

*Receptors

Lipoxin

Receptors

Peptide/immunology

Stomach Neoplasms/etiology

Publication and Content Type

ref (subject category)

art (subject category)