Renin-angiotensin system promotes colonic inflammation by inducing T17 activation via JAK2/STAT pathway.

Authors:
Lei He
Lei He
College of Veterinary Medicine
China
Jie Du
Jie Du
Beijing Anzhen Hospital
China
Yinyin Chen
Yinyin Chen
Changchun Institute of Applied Chemistry
China
Chunyan Liu
Chunyan Liu
State Key Laboratory of Atmospheric Boundary Layer Physics and Atmospheric Chemistry
United States
Min Zhou
Min Zhou
Nanjing Drum Tower Hospital
Nanjing Shi | China
David T Rubin
David T Rubin
University of Chicago
United States
Joel Pekow
Joel Pekow
University of Chicago
United States

Am J Physiol Gastrointest Liver Physiol 2019 Jun 17;316(6):G774-G784. Epub 2019 Apr 17.

Department of Medicine, Division of Biological Sciences, The University of Chicago , Chicago, Illinois.

Previous studies suggest that the renin-angiotensin system (RAS) is a pathogenic factor for colitis. The goal of this study was to elucidate the molecular mechanism whereby angiotensin II (ANG II) promotes colonic inflammation. We found that renin was highly induced in colonic biopsies from patients with ulcerative colitis or Crohn's disease, and colonic renin and ANG II levels were markedly increased in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, indicating that the colonic RAS is activated in colitis. Renin transgenic (RenTg) mice exhibited increased phosphorylation in Janus kinase-2 (JAK2) and signal transducer and activator of transcription1/3 (STAT1/3) within colonic mucosa at baseline and following TNBS induction, suggesting that ANG II promotes colonic inflammation via the JAK2/STAT1/3 pathway. Treatment with pan-JAK inhibitor tofacitinib blocked JAK2 and STAT1/3 phosphorylation, attenuated T helper (T)1 and T17 responses, alleviated colitis, and prevented death of RenTg mice in TNBS model. ANG II stimulated JAK2/STAT1/3 phosphorylation in both Jurkat T lymphocytes and HCT116 epithelial cells. In vitro polarization assays demonstrated that ANG II directly promoted T17 polarization, but not T1 polarization, via JAK2/STAT1/3. ANG II stimulation of transforming growth factor-β1 (TGFβ1), IL-6, myosin light chain kinase, and p53 upregulated modulator of apoptosis in HCT116 cells was also mediated by JAK2/STAT1/3. These observations suggest that ANG II promotes T17 polarization directly as well as indirectly by inducing production of T17-polarizing cytokines (e.g., TGFβ1 and IL-6) from colonic epithelial cells, both via the JAK2/STAT pathway. Therefore, colonic RAS promotes colonic inflammation, at least in part, by stimulating T17 activation. This study demonstrates that the local renin-angiotensin system in the colon is activated in colitis development, which promotes mucosal T helper cell activation through the JAK2/STAT pathway. These observations provide molecular evidence that the renin-angiotensin system is a pathogenic factor for the development of inflammatory bowel diseases.

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http://dx.doi.org/10.1152/ajpgi.00053.2019DOI Listing
June 2019
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References

(Supplied by CrossRef)
Article in Lab Invest
Cooper HS et al.
Lab Invest 1993

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