Phosphoinositide 3‑kinase δ/γ inhibition does not prevent concanavalin A‑induced hepatitis

Liu,Yuanyuan; Xiong,Li; Chang,Ying; Tang,Jianying; Ang,Wei; Yang,Tao; Pi,Weiyi; Yang,Xiaoyan; Ye,Weiwei; Luo,Youfu; Wang,Zhenling

doi:10.3892/mmr.2013.1649

Phosphoinositide 3‑kinase δ/γ inhibition does not prevent concanavalin A‑induced hepatitis

Authors:
- Yuanyuan Liu
- Li Xiong
- Ying Chang
- Jianying Tang
- Wei Ang
- Tao Yang
- Weiyi Pi
- Xiaoyan Yang
- Weiwei Ye
- Youfu Luo
- Zhenling Wang
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Affiliations: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, P.R. China
Published online on: August 22, 2013 https://doi.org/10.3892/mmr.2013.1649
Pages: 1305-1310

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Abstract

An increasing number of studies have suggested that phosphoinositide 3‑kinase‑γ (PI3Kγ) and PI3Kδ are involved in the pathogenesis of autoimmune and inflammatory diseases, such as asthma and atherosclerosis. However, the underlying mechanism of acute hepatitis remains unknown. The present study aimed to determine the effect of PI3Kδ/γ inhibition on hepatic injury in a murine model of hepatitis induced by concanavalin A (ConA). It was demonstrated that the pharmacological inhibition of PI3Kδ/γ by TG100‑115 did not prevent liver damage following ConA challenge. Furthermore, the PI3Kδ/γ inhibition resulted in elevated transaminase activity in the serum, aggravated hepatic lesions characterized by hepatic necrosis, increased inflammatory cell infiltration and apoptosis of hepatocytes. Survival tests demonstrated that TG100‑115 significantly increased the death rate of mice following ConA challenge. In addition, TG100‑115 increased the serum levels of the proinflammatory cytokine IL‑2 following ConA injection. These results may oppose the development of PI3Kδ/γ inhibitors as therapeutic agents, particularly for the treatment of human hepatitis.

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