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@article{Powell:2020:10.1136/gutjnl-2019-318483,
author = {Powell, N and Pantazi, E and Tsamaki, A and Pavlidis, P and Li, K and Yang, F and Parker, A and Pin, C and Cozzetto, D and Minns, DH and Stolarczyk, E and Savelijeva, S and Mohamed, R and Lavender, P and Afzali, B and Digby-Bell, J and Tsui, T and Kaser, A and Friedman, J and MacDonald, TT and Bewick, GA and Lord, GM},
doi = {10.1136/gutjnl-2019-318483},
journal = {Gut},
pages = {478--490},
title = {Interleukin 22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells},
url = {http://dx.doi.org/10.1136/gutjnl-2019-318483},
volume = {69},
year = {2020}
}
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TY  - JOUR
AB  - Objective - The functional role of interleukin-22 (IL22) in chronic inflammation is controversial and mechanistic  insights  into  how  it  regulates  target  tissue  are  lacking.  In  this  study,  we evaluated the  functional  role  of  IL22  in  chronic  colitis  and  probed  mechanisms  of  IL22- mediated regulation of colonic epithelial cells. Design – To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial  cells  we  employed a  3-dimentional  mini-gut  epithelial  organoid system,in  vivo disease models and transcriptomic datasets in human IBD. Results - As well as inducing transcriptional modules implicated in anti-microbial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional program in colonic epithelial cells. In the  colon of patients  with active  colonic Crohn’s  disease  (CD), there  was  enrichment  of  IL22-responsive transcriptional  modules  and ER  stress response modules.  Strikingly,  in  an  IL22-dependent  model  of chronic colitis, targeting IL22 alleviated   colonic  epithelial  ER  stress and  attenuated colitis.  Pharmacological  modulation of  the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. Conclusions- Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in  IBD  and provide novel  insights  into  the  molecular  mechanisms  of  IL22-mediated pathogenicity  in  chronic  colitis.  Targeting  IL22 regulated  pathways  and alleviating  colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis
AU  - Powell,N
AU  - Pantazi,E
AU  - Tsamaki,A
AU  - Pavlidis,P
AU  - Li,K
AU  - Yang,F
AU  - Parker,A
AU  - Pin,C
AU  - Cozzetto,D
AU  - Minns,DH
AU  - Stolarczyk,E
AU  - Savelijeva,S
AU  - Mohamed,R
AU  - Lavender,P
AU  - Afzali,B
AU  - Digby-Bell,J
AU  - Tsui,T
AU  - Kaser,A
AU  - Friedman,J
AU  - MacDonald,TT
AU  - Bewick,GA
AU  - Lord,GM
DO  - 10.1136/gutjnl-2019-318483
EP  - 490
PY  - 2020///
SN  - 0017-5749
SP  - 478
TI  - Interleukin 22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells
T2  - Gut
UR  - http://dx.doi.org/10.1136/gutjnl-2019-318483
UR  - https://gut.bmj.com/content/69/3/578
VL  - 69
ER  -
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