Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2015; 21(20): 6180-6193
Published online May 28, 2015. doi: 10.3748/wjg.v21.i20.6180
SGK1 inhibits cellular apoptosis and promotes proliferation via the MEK/ERK/p53 pathway in colitis
Jian-An Bai, Gui-Fang Xu, Li-Jun Yan, Wei-Wen Zeng, Qian-Qian Ji, Jin-Dao Wu, Qi-Yun Tang
Jian-An Bai, Gui-Fang Xu, Li-Jun Yan, Wei-Wen Zeng, Qian-Qian Ji, Jin-Dao Wu, Qi-Yun Tang, Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Author contributions: Bai JA and Xu GF contributed equally to this study; Bai JA, Xu GF and Tang QY designed the research; Bai JA and Xu GF performed the research; Yan LJ, Ji QQ, Zeng WW and Wu JD contributed to the model establishment or analytic tools; Bai JA analyzed the data; Bai JA, Xu GF and Tang QY wrote the paper.
Supported by National Natural Science Foundation of China, No. 81470806; the National Natural Science Foundation of Jiangsu Province, No. BK20141496; and the Public Health Ministry of Jiangsu Province in the Talents in Medical Science Program, No. RC201179.
Ethics approval: The study was reviewed and approved by the First Affiliated Hospital of Nanjing Medical University Institutional Review Board.
Institutional animal care and use committee: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Nanjing Medical University.
Conflict-of-interest: No conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Qi-Yun Tang, MD, PhD, Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Rd, Nanjing 210029, China. tqy831@163.com
Telephone: +86-25-68136542 Fax: +86-25-83674636
Received: October 12, 2014
Peer-review started: October 13, 2014
First decision: November 14, 2014
Revised: December 12, 2014
Accepted: February 12, 2015
Article in press: February 13, 2015
Published online: May 28, 2015
Processing time: 230 Days and 2.7 Hours
Abstract

AIM: To investigate the role of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in colitis and its potential pathological mechanisms.

METHODS: SGK1 expression in mucosal biopsies from patients with active Crohn’s disease (CD) and normal controls was detected by immunohistochemistry. We established an acute colitis model in mice induced by 2,4,6-trinitrobenzene sulfonicacid, and demonstrated the presence of colitis using the disease activity index, the histologic activity index and hematoxylin and eosin staining. The cellular events and potential mechanisms were implemented with small interference RNA and an inhibitor of signaling molecule (i.e., U0126) in intestinal epithelial cells (IECs). The interaction between SGK1 and the signaling molecule was assessed by co-immunoprecipitation.

RESULTS: SGK1 expression was significantly increased in the inflamed epithelia of patients with active CD and TNBS-induced colitis model (0.58 ± 0.055 vs 0.85 ± 0.06, P < 0.01). At the cellular level, silencing of SGK1 by small interference RNA (siSGK1) significantly inhibited the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1) and the downstream molecule extracellular signal regulated protein kinase (ERK) 1/2, which induced the upregulation of p53 and Bcl-2-associated X protein, mediating the subsequent cellular apoptosis and proliferation in IECs. Cells treated with MEK1 inhibitor (i.e., U0126) before siSGK1 transfection showed a reversal of the siSGK1-induced cellular apoptosis.

CONCLUSION: Our data suggested that SGK1 may protect IECs in colitis from tumor necrosis factor-α-induced apoptosis partly by triggering MEK/ERK activation.

Keywords: Colitis; Serum-and-glucocorticoid-inducible-kinase-1; MEK/ERK; Apoptosis; p53

Core tip: This study showed that serum-and-glucocorticoid-inducible-kinase-1 (SGK1) expression was significantly increased in the inflamed epithelia of patients with active Crohn’s disease (CD) in a TNBS-induced colitis model. At the cellular level, silencing of SGK1 inhibited the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1) and the downstream molecule ERK1/2, which induced the upregulation of p53 and Bcl-2-associated X protein, triggering subsequent cellular apoptosis and inhibition of proliferation in intestinal epithelial cells. A MEK1 inhibitor (i.e., U0126) was used to show that this was a MEK/ERK-dependent process. Co-immunoprecipitation analysis uncovered the mechanism of the interaction between SGK1 and MEK1. Our results provide a new therapeutic approach to CD therapy.