IL-22 negatively regulates Helicobacter pylori-induced CCL20 expression in gastric epithelial cells.
Helicobacter pylori is a Gram-negative bacterium that infects the human gastric mucosa and causes various gastric diseases. H. pylori infection induces the production of inflammatory chemokine CCL20 in gastric mucosa and leads to gastric inflammation. Given that the IL-22/IL-22R axis plays a critical role in the regulation of homeostasis and inflammation of epithelial cells at barrier surfaces, we investigated the effect of IL-22 on CCL20 expression induced by H. pylori. We demonstrated that H. pylori infection of the gastric epithelia-derived AGS cells significantly induced CCL20 expression and the induction was inhibited by IL-22. Functional analysis of the CCL20 promoter revealed that the H. pylori-induced CCL20 expression required the activation of NF-κB, and that IL-22 inhibited the induction by attenuating NF-κB activation. Knockdown of endogenous STAT3 by either short interfering RNAs or a short hairpin RNA significantly reduced the inhibitory effect of IL-22. Furthermore, STAT3 phosphorylation elicited by IL-22 was crucial for the inhibition of H. pylori-induced CCL20 expression. Consistent with the in vitro data showing that IL-22 negatively regulated H. pylori-induced CCL20 expression in gastric epithelial cells, studies on the tissue sections from patients with H. pylori infection also revealed an inverse association of IL-22 expression and CCL20 expression in vivo. Together, our findings suggest that IL-22 plays a role in the control of overproduction of the inflammatory chemokine and thus may protect the gastric mucosa from inflammation-mediated damage.
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
Jia-Perng
JP
Chen
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Ming-Shiang
MS
Wu
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Cancer Research Center and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Sung-Hsin
SH
Kuo
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Fang
F
Liao
D015153:Blotting, Western; D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology*; D016480:Helicobacter pylori / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007378:Interleukins / Q000494:pharmacology*; D008156:Luciferases; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097043:Interleukin-22
D054418:Chemokine CCL20; D017931:DNA Primers; D007378:Interleukins; D008156:Luciferases; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C108355:CCL20 protein, human; C494086:STAT3 protein, human