IL-21 is highly produced in Helicobacter pylori-infected gastric mucosa and promotes gelatinases synthesis.
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-kappaB but not MAPK activation, and inhibition of NF-kappaB 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.
Caruso
Roberta
R
Department of Internal Medicine and Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University of Rome Tor Vergata, Rome, Italy.
Fina
Daniele
D
Peluso
Ilaria
I
Fantini
Massimo Claudio
MC
Tosti
Claudio
C
Del Vecchio Blanco
Giovanna
G
Paoluzi
Omero Alessandro
OA
Caprioli
Flavio
F
Andrei
Fabio
F
Stolfi
Carmine
C
Romano
Marco
M
Ricci
Vittorio
V
MacDonald
Thomas T
TT
Pallone
Francesco
F
Monteleone
Giovanni
G
D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D005753:Gastric Mucosa / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D005756:Gastritis / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D018093:Gelatinases / Q000378:metabolism*; D016481:Helicobacter Infections / Q000201:enzymology / Q000276:immunology*; D016480:Helicobacter pylori; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D000098546:Interleukin-21
D000906:Antibodies; D007378:Interleukins; D016328:NF-kappa B; D053655:Receptors, Interleukin-21; D020929:Mitogen-Activated Protein Kinase Kinases; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000098546:Interleukin-21