Expression and roles of TIPE2 in autoimmune hepatitis

Qian,Jinhua; Meng,Zongde; Guan,Jiachang; Zhang,Zhiwei; Wang,Yangang

doi:10.3892/etm.2017.4050

Expression and roles of TIPE2 in autoimmune hepatitis

Authors:
- Jinhua Qian
- Zongde Meng
- Jiachang Guan
- Zhiwei Zhang
- Yangang Wang
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Affiliations: Department of Spleen and Stomach Diseases, Hebei Province Hospital of Traditional Chinese Medicine, Shijiazhuang, Hebei 050011, P.R. China, Department of Traditional Chinese Medicine, Graduate School, Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Department of Digestive Tract Medicine, Hebei Yiling Hospital, Shijiazhuang, Hebei 050091, P.R. China
Published online on: January 16, 2017 https://doi.org/10.3892/etm.2017.4050
Pages: 942-946
Copyright: © Qian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tumor necrosis factor, alpha‑induced protein 8‑like 2 (TIPE2) is associated with the development of hepatic inflammatory diseases. However, to date, the possible role of TIPE2 in autoimmune hepatitis (AIH) has not been reported. The present study aimed to investigate the expression of TIPE2 in peripheral blood mononuclear cells (PBMCs) of mice with AIH. Furthermore, the liver function, pro‑inflammatory cytokine production and hepatic histopathology were examined in TIPE2‑deficient mice in order to evaluate whether TIPE2 is involved in the pathogenesis of AIH. A murine model of AIH was induced by treatment with concanavalin A (ConA). The expression of TIPE family members in the PBMCs was examined using reverse‑transcription quantitative polymerase chain reaction analysis, while the protein expression of TIPE2 was additionally detected by western blot analysis. The activity of alanine amiotransferase (ALT) and aspartate aminotransferase (AST) in the serum was measured on an automated chemical analyzer to assess liver function. The serum levels of tumor necrosis factor‑α, interleukin (IL)‑6 and IL‑12 were measured using commercial ELISA kits. Hematoxylin and eosin staining was performed to assess hepatic histopathology. The results showed that the expression of TIPE2 was significantly decreased in the mice with AIH. Following ConA‑induced AIH, TIPE2‑deficient mice had significantly increased serum ALT and AST levels, enhanced production of pro‑inflammatory cytokines, as well as more severe hepatic inflammation compared with the wild‑type mice. In conclusion, the present study demonstrated, for the first time, that TIPE2 is involved in the pathogenesis of AIH. TIPE2 prevents liver dysfunction and inhibits deleterious inflammatory immune responses after AIH and may therefore serve as a novel agent for the treatment of AIH.

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1	Vergani D and Mieli-Vergani G: Aetiopathogenesis of autoimmune hepatitis. World J Gastroenterol. 14:3306–3312. 2008. View Article : Google Scholar : PubMed/NCBI
2	Verma S, Maheshwari A and Thuluvath P: Liver failure as initial presentation of autoimmune hepatitis: Clinical characteristics, predictors of response to steroid therapy, and outcomes. Hepatology. 49:1396–1397. 2009. View Article : Google Scholar : PubMed/NCBI
3	Strassburg CP: Autoimmune hepatitis. Dig Dis. 31:155–163. 2013. View Article : Google Scholar : PubMed/NCBI
4	Lapierre P, Béland K, Yang R and Alvarez F: Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance. Hepatology. 57:217–227. 2013. View Article : Google Scholar : PubMed/NCBI
5	Wong RJ, Gish R, Frederick T, Bzowej N and Frenette C: The impact of race/ethnicity on the clinical epidemiology of autoimmune hepatitis. J Clin Gastroenterol. 46:155–161. 2012. View Article : Google Scholar : PubMed/NCBI
6	Schramm C, Kanzler S, zum Büschenfelde KH, Galle PR and Lohse AW: Autoimmune hepatitis in the elderly. Am J Gastroenterol. 96:1587–1591. 2001. View Article : Google Scholar : PubMed/NCBI
7	Abe M, Mashiba T, Zeniya M, Yamamoto K, Onji M and Tsubouchi H: Autoimmune Hepatitis Study Group-Subgroup of the Intractable Hepato-Biliary Disease Study Group in Japan: Present status of autoimmune hepatitis in Japan: A nationwide survey. J Gastroenterol. 46:1136–1141. 2011. View Article : Google Scholar : PubMed/NCBI
8	Peng M, Li Y, Zhang M, Jiang Y, Xu Y, Tian Y, Peng F and Gong G: Clinical features in different age groups of patients with autoimmune hepatitis. Exp Ther Med. 7:145–148. 2014.PubMed/NCBI
9	Muratori P, Granito A, Quarneti C, Ferri S, Menichella R, Cassani F, Pappas G, Bianchi FB, Lenzi M and Muratori L: Autoimmune hepatitis in Italy: The Bologna experience. J Hepatol. 50:1210–1218. 2009. View Article : Google Scholar : PubMed/NCBI
10	Chen J, Eslick GD and Weltman M: Systematic review with meta-analysis: Clinical manifestations and management of autoimmune hepatitis in the elderly. Aliment Pharmacol Ther. 39:117–124. 2014. View Article : Google Scholar : PubMed/NCBI
11	Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, et al: TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell. 133:415–426. 2008. View Article : Google Scholar : PubMed/NCBI
12	Lou Y and Liu S: The TIPE (TNFAIP8) family in inflammation, immunity, and cancer. Mol Immunol. 49:4–7. 2011. View Article : Google Scholar : PubMed/NCBI
13	Zhang G, Hao C, Lou Y, Xi W, Wang X, Wang Y, Qu Z, Guo C, Chen Y, Zhang Y and Liu S: Tissue-specific expression of TIPE2 provides insights into its function. Mol Immunol. 47:2435–2442. 2010. View Article : Google Scholar : PubMed/NCBI
14	Zhang L, Shi Y, Wang Y, Zhu F, Wang Q, Ma C, Chen YH and Zhang L: The unique expression profile of human TIPE2 suggests new functions beyond its role in immune regulation. Mol Immunol. 48:1209–1215. 2011. View Article : Google Scholar : PubMed/NCBI
15	Zhang X, Wang J, Fan C, Li H, Sun H, Gong S, Chen YH and Shi Y: Crystal structure of TIPE2 provides insights into immune homeostasis. Nat Struct Mol Biol. 16:89–90. 2009. View Article : Google Scholar : PubMed/NCBI
16	Sun H, Zhuang G, Chai L, Wang Z, Johnson D, Ma Y and Chen YH: TIPE2 controls innate immunity to RNA by targeting the phosphatidylinositol 3-kinase-Rac pathway. J Immunol. 189:2768–2773. 2012. View Article : Google Scholar : PubMed/NCBI
17	Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q, Guo W and Chen YH: TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA. 109:15413–15418. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lou Y, Liu S, Zhang C, Zhang G, Li J, Ni M, An G, Dong M, Liu X, Zhu F, et al: Enhanced atherosclerosis in TIPE2-deficient mice is associated with increased macrophage responses to oxidized low-density lipoprotein. J Immunol. 191:4849–4857. 2013. View Article : Google Scholar : PubMed/NCBI
19	Cao X, Zhang L, Shi Y, Sun Y, Dai S, Guo C, Zhu F, Wang Q, Wang J, Wang X, et al: Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol Cancer. 12:1492013. View Article : Google Scholar : PubMed/NCBI
20	Zhang YH, Yan HQ, Wang F, Wang YY, Jiang YN, Wang YN and Gao FG: TIPE2 inhibits TNF-α-induced hepatocellular carcinoma cell metastasis via Erk1/2 downregulation and NF-κB activation. Int J Oncol. 46:254–264. 2015.PubMed/NCBI
21	Zhang W, Zhang J, Zhao L, Shao J, Cui J, Guo C, Zhu F, Chen YH and Liu S: TIPE2 protein negatively regulates HBV-specific CD8⁺ T lymphocyte functions in humans. Mol Immunol. 64:204–209. 2015. View Article : Google Scholar : PubMed/NCBI
22	Xi W, Hu Y, Liu Y, Zhang J, Wang L, Lou Y, Qu Z, Cui J, Zhang G, Liang X, et al: Roles of TIPE2 in hepatitis B virus-induced hepatic inflammation in humans and mice. Mol Immunol. 48:1203–1208. 2011. View Article : Google Scholar : PubMed/NCBI
23	Kong L, Liu K, Zhang YZ, Jin M, Wu BR, Wang WZ, Li W, Nan YM and Chen YH: Downregulation of TIPE2 mRNA expression in peripheral blood mononuclear cells from patients with chronic hepatitis C. Hepatol Int. 7:844–849. 2013. View Article : Google Scholar : PubMed/NCBI
24	Wang LY, Fan YC, Zhao J, Gao S, Sun FK, Han J, Yang Y and Wang K: Elevated expression of tumour necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 mRNA in peripheral blood mononuclear cells is associated with disease progression of acute-on-chronic hepatitis B liver failure. J Viral Hepat. 21:64–73. 2014. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Gus-Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S, Zhang L and Chen YH: The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell. 45:610–618. 2012. View Article : Google Scholar : PubMed/NCBI
27	Zhang Z, Liang X, Gao L, Ma H, Liu X, Pan Y, Yan W, Shan H, Wang Z, Chen YH and Ma C: TIPE1 induces apoptosis by negatively regulating Rac1 activation in hepatocellular carcinoma cells. Oncogene. 34:2566–2574. 2015. View Article : Google Scholar : PubMed/NCBI
28	Fayngerts SA, Wu J, Oxley CL, Liu X, Vourekas A, Cathopoulis T, Wang Z, Cui J, Liu S, Sun H, et al: TIPE3 is the transfer protein of lipid second messengers that promote cancer. Cancer Cell. 26:465–478. 2014. View Article : Google Scholar : PubMed/NCBI
29	Tiegs G, Hentschel J and Wendel A: A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 90:196–203. 1992. View Article : Google Scholar : PubMed/NCBI
30	Shao X, Qian Y, Xu C, Hong B, Xu W, Shen L, Jin C, Wu Z, Tong X and Yao H: The protective effect of intrasplenic transplantation of Ad-IL-18BP/IL-4 gene-modified fetal hepatocytes on ConA-induced hepatitis in mice. PLoS One. 8:e588362013. View Article : Google Scholar : PubMed/NCBI
31	Ichiki Y, Aoki CA, Bowlus CL, Shimoda S, Ishibashi H and Gershwin ME: T cell immunity in autoimmune hepatitis. Autoimmun Rev. 4:315–321. 2005. View Article : Google Scholar : PubMed/NCBI