Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2015; 21(48): 13438-13446
Published online Dec 28, 2015. doi: 10.3748/wjg.v21.i48.13438
Sphingosine kinase 1 dependent protein kinase C-δ activation plays an important role in acute liver failure in mice
Yan-Chang Lei, Ling-Ling Yang, Wen Li, Pan Luo
Yan-Chang Lei, Department of Infectious Diseases, Zhejiang Hospital, Hangzhou 310013, Zhejiang Province, China
Yan-Chang Lei, Ling-Ling Yang, Wen Li, Pan Luo, Infectious Disease Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Author contributions: Lei YC designed the research; Lei YC, Yang LL, Wen Li and Luo P performed the research and analyzed the data; Lei YC wrote the paper.
Supported by The National Natural Science Foundation of China, No. 81160065.
Institutional review board statement: The study was reviewed and approved by the Zhejiang Hospital Institutional Review Board.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Zhejiang Hospital.
Conflict-of-interest statement: We declare that there are no conflicts of interest to disclose.
Data sharing statement: No additional data are available.
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: Yan-Chang Lei, Chief Physician, Department of Infectious Diseases, Zhejiang Hospital, 12 Lingyin Road, Hangzhou 310013, Zhejiang Province, China. ycleihust@sina.com
Telephone: +86-571-81595081 Fax: +86-571-87980175
Received: October 19, 2015
Peer-review started: October 20, 2015
First decision: November 9, 2015
Revised: November 12, 2015
Accepted: November 19, 2015
Article in press: November 19, 2015
Published online: December 28, 2015
Abstract

AIM: To investigate the role of protein kinase C (PKC)-δ activation in the pathogenesis of acute liver failure (ALF) in a well-characterized mouse model of D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced ALF.

METHODS: BALB/c mice were randomly assigned to five groups, and ALF was induced in mice by intraperitoneal injection of D-GaIN (600 mg/kg) and LPS (10 μg/kg). Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at different time points within one week were determined using a multiparameteric analyzer. Serum levels of high-mobility group box 1 (HMGB1), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 as well as nuclear factor (NF)-κB activity were determined by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of PKC-δ in liver tissue and peripheral blood mononuclear cells (PBMCs) was analyzed by Western blot.

RESULTS: The expression and activation of PKC-δ were up-regulated in liver tissue and PBMCs of mice with D-GalN/LPS-induced ALF. Inhibition of PKC-δ activation with rottlerin significantly increased the survival rates and decreased serum ALT/AST levels at 6, 12 and 24 h compared with the control group (P < 0.001). Rottlerin treatment also significantly decreased serum levels of HMGB1 at 6, 12, and 24 h, TNF-α, IL-6 and IL-1 β at 12 h compared with the control group (P < 0.01). The inflammatory cell infiltration and necrosis in liver tissue were also decreased in the rottlerin treatment group. Furthermore, sphingosine kinase 1 (SphK1) dependent PKC-δ activation played an important role in promoting NF-κB activation and inflammatory cytokine production in ALF.

CONCLUSION: SphK1 dependent PKC-δ activation plays an important role in promoting NF-κB activation and inflammatory response in ALF, and inhibition of PKC-δ activation might be a potential therapeutic strategy for this disease.

Keywords: Acute liver failure, Protein kinase C-δ, Sphingosine kinase 1, Nuclear factor-κB

Core tip: In this study, we found protein kinase C (PKC)-δ expression and activation in liver tissue or peripheral blood mononuclear cells of mice with acute liver failure (ALF). Inhibition of PKC-δ activation attenuated ALF in this animal model. Furthermore, sphingosine kinase 1 (SphK1) was required for PKC-δ activation in LPS-stimulated macrophages and the ALF mouse model. Our findings suggest that SphK1 dependent PKC-δ activation plays an important role in ALF, and inhibition of PKC-δ activation might be a potential therapeutic strategy for this disease.