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* Department of Internal Medicine and Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University of Rome "Tor Vergata," Rome, Italy;
Department of Internal and Experimental Medicine-Surgery, Second University of Naples, Naples, Italy;
Department of Experimental Medicine, University of Pavia, Pavia, Italy; and
Institute of Cell and Molecular Science, Barts and the London, Queen Mary’s School of Medicine and Dentistry, London, United Kingdom
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-
B but not MAPK activation, and inhibition of NF-B 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.
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 by the "Fondazione Umberto di Mario," by Grant IBD-0154R from the Broad Medical Research Program Foundation, and by Giuliani Societá per Azioni (Milan, Italy).
2 Address correspondence and reprint requests to Dr. Giovanni Monteleone, Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. E-mail address: Gi.Monteleone{at}med.uniroma2.it
3 Abbreviations used in this paper: Hp, Helicobacter pylori; MMP, matrix metalloproteinase; TIMP, tissue inhibitors of MMP; 
c, common -chain; T-LPL, T lamina propria lymphocyte; TPCK, N-p-tosyl-L-phenylalanine chloromethyl ketone; a.u., arbitrary unit.
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