Author:
Xiao Yongtao,Lu Ying,Wang Ying,Yan Weihui,Cai Wei
Abstract
AbstractThe regenerating islet-derived family member 4 (Reg4) in the gastrointestinal tract is up-regulated during
intestinal inflammation. However, the physiological function of Reg4 in the inflammation is largely unknown. In the
current study, the functional roles and involved mechanisms of intestinal epithelial
Reg4 in intestinal inflammation were studied
in healthy and inflamed states using human intestinal specimens, an intestinal
conditional Reg4 knockout mouse (Reg4ΔIEC) model and dextran sulfate sodium
(DSS)-induced colitis model. We showed that the elevated serum Reg4 in pediatric intestinal failure (IF) patients were
positively correlated with the serum concentrations of proinflammatory cytokines
interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In inflamed intestine
of IF patients, the crypt base Reg4 protein was
increased and highly expressed towards the luminal face. The Reg4 was indicated as a novel target of activating transcription
factor 2 (ATF2) that enhanced Reg4 expression
during the intestinal inflammation. In vivo, the DSS-induced colitis was
significantly ameliorated in Reg4ΔIEC mice. Reg4ΔIEC mice altered the colonic bacterial composition
and reduced the bacteria adhere to the colonic epithelium. In vitro, Reg4 was showed to promote the growth of colonic
organoids, and that this occurs through a mechanism involving activation of signal
transducer and activator of transcription 3 (STAT3). In conclusion, our findings
demonstrated intestinal-epithelial Reg4
deficiency protects against experimental colitis and mucosal injury via a mechanism
involving alteration of bacterial homeostasis and STAT3 activation.
Publisher
Springer Science and Business Media LLC
Subject
Immunology,Immunology and Allergy
Cited by
12 articles.
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