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* Divisione di Immunologia Clinica ed Allergologia e Centro Interdipartimentale di Ricerca di Scienze Immunologiche di Base e Cliniche,
Dipartimento di Biologia e Patologia Cellulare e Molecolare,
Dipartimento di Scienze Biomorfologiche e Funzionali, Sezione di Patologia, and
Dipartimento di Medicina Clinica e Sperimentale, Gastroenterologia, Università di Napoli Federico II, Naples, Italy;
¶ Dipartimento di Fisiologia, Sezione di Fisiologia Umana, Università di Pavia, Pavia, Italy; and
|| Dipartimento Medico Chirurgico di Internistica Clinica e Sperimentale e Centro Interuniversitario di Richerche su Alimenti, Nutrizione e Apparato Digerente, Seconda Università di Napoli, Naples, Italy
Helicobacter pylori-derived peptide RpL1 aa 2–20 (Hp(2–20)) in addition to its antimicrobial action exerts several immunomodulatory effects in eukaryotic cells by interacting with formyl peptide receptors (FPRs). It has recently been shown that activation of FPRs facilitates intestinal epithelial cell restitution. We investigated whether Hp(2–20) induces healing of injured gastric mucosa and assessed the mechanisms underlying any such effect. We investigated the expression of FPRs in two gastric epithelial cell lines (MKN-28 and AGS) at mRNA and protein level. To determine whether FPRs were functional we performed chemotaxis experiments and proliferation assays and studied the Hp(2–20)-activated downstream signaling pathway. The effect of Hp(2–20) on mucosal healing was evaluated in rats after indomethacin-induced injury. Here we show that: (1) FPRs were expressed in both cell lines; (2) Hp(2–20) stimulated migration and proliferation of gastric epithelial cells; (3) this effect was specifically mediated by formyl peptide receptor-like 1 (FPRL1) and FPRL2 and was associated with activation of FPR-related downstream signaling pathways; (4) Hp(2–20) up-regulated the expression and secretion of vascular endothelial growth factor; and (5) Hp(2–20) accelerated healing of rat gastric mucosa after injury brought about by indomethacin at both the macroscopic and microscopic levels. In conclusion, by interacting with FRPL1 and FPRL2, H. pylori-derived Hp(2–20) induces cell migration and proliferation, as well as the expression of vascular endothelial growth factor, thereby promoting gastric mucosal healing. This study provides further evidence of the complexity of the relationship between H. pylori and human gastric mucosa, and it suggests that a bacterial product may be used to heal gastric mucosal injury.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the Ministero dell’Istruzione, Università e Ricerca National Project "Role of cells of innate immunity in the pathogenesis of Helicobacter pylori disease".
2 Address correspondence and reprint requests to Dr. Amato de Paulis, Department of Clinical Immunology and Allergy, University of Naples Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy. E-mail address: depaulis{at}unina.it
3 Abbreviations used in this paper: EGF, epidermal growth factor; BCF, broth culture filtrate; CsH, cyclosporin H; FPR, N-formyl peptide receptor; FPRL1, formyl peptide receptor-like 1; FPRL2, formyl peptide receptor-like 2; VacA, vacuolating cytotoxin; VEGF, vascular endothelial growth factor; WKYMVm, hexapeptide Trp-Lys-Tyr-Met-Val-D-Met-NH2.
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