IL-21 Is Highly Produced in Helicobacter pylori-Infected Gastric Mucosa and Promotes Gelatinases Synthesis

Abstract

Helicobacter pylori (Hp) infection is associated with gastric inflammation and ulceration. The pathways of tissue damage in Hp-infected subjects are complex, but evidence indicates that T cell-derived cytokines enhance the synthesis of matrix metalloproteinases (MMP) that contribute to mucosal ulceration and epithelial damage. In this study, we have examined the role of the T cell cytokine IL-21 in Hp-infected gastric mucosa and evaluated whether IL-21 regulates MMP production by gastric epithelial cells. We show that IL-21 is constitutively expressed in gastric mucosa and is more abundant in biopsy specimens and purified mucosal CD3+ T cells from Hp-infected patients compared with normal patients and disease controls. We also demonstrate that IL-21R is expressed by primary gastric epithelial cells, as well as by the gastric epithelial cell lines AGS and MKN28. Consistently, AGS cells respond to IL-21 by increasing production of MMP-2 and MMP-9, but not MMP-1, MMP-3, MMP-7, or tissue inhibitors of MMP. Analysis of signaling pathways leading to MMP production reveals that IL-21 enhances NF-κB but not MAPK activation, and inhibition of NF-κB activation reduces IL-21-induced MMP-2 and MMP-9 production. Finally, we show that treatment of Hp-infected gastric explants with anti-IL-21 reduces epithelial cell-derived MMP-2 and MMP-9 production. These data indicate that IL-21 is overexpressed in Hp-infected gastric mucosa where it could contribute to increased epithelial gelatinase production.

Helicobacter pylori Hp(2–20) Promotes Migration and Proliferation of Gastric Epithelial Cells by Interacting with Formyl Peptide Receptors In Vitro and Accelerates Gastric Mucosal Healing In Vivo

“…MKN-28 and AGS cells were grown as monolayer in DMEM (Invitrogen) supplemented with 10% FCS, 100 U/ml penicillin G sodium, and 100 g/ml streptomycin sulfate at 37°C in a humidified atmosphere of 5% CO 2 (15). To induce VEGF-A protein, we incubated cells in medium supplemented with 5% FCS to maintain stability of the protein (16).…”

“…We examined FPR, FPRL1, and FPRL2 expression at mRNA and protein level in human gastric epithelial cells derived from a welldifferentiated human gastric tubular adenocarcinoma (i.e., MKN-28 cells) and from a poorly differentiated human gastric adenocarcinoma (i.e., AGS cells) (15). Monocytes were used as a control (23).…”

“…We therefore tested whether fMLP and Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) could also induce cell proliferation. To address this point, we mea- …”

“…Therefore, this study was designed: (1) to assess whether gastric epithelial cell lines express FPRs; (2) to investigate whether Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) stimulates cell migration and proliferation and VEGF expression and release in gastric epithelial cell lines; (3) to investigate the role of FPRs in any such effect(s); and (4) to evaluate whether Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) accelerates healing in a rat model of indomethacin-induced gastric mucosal damage.…”

L’interleukine-21, une cytokine clé dans le contrôle du VIH et d’autres infections virales chroniques

“…L'IL-21R est un hétérodimère constitué d'une chaîne  (IL-21R) et d'une chaîne gamma commune ( c ). Il est principalement exprimé par les cellules T CD4 + , CD8 + , les cellules B, les cellules dendritiques, les macrophages, les cellules NK et les kératinocytes [4][5][6][7][8][9]. L'IL-21 possède donc un rôle pléïotrope sur les différentes composantes de la réponse immunitaire (Tableau I).…”