title: Phosphoinositide 3-kinase δ/γ inhibition does not prevent concanavalin A-induced hepatitis.
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.
authors: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors: Yuanyuan
authors: Y
authors: Liu
authors: Li
authors: L
authors: Xiong
authors: Ying
authors: Y
authors: Chang
authors: Jianying
authors: J
authors: Tang
authors: Wei
authors: W
authors: Ang
authors: Tao
authors: T
authors: Yang
authors: Weiyi
authors: W
authors: Pi
authors: Xiaoyan
authors: X
authors: Yang
authors: Weiwei
authors: W
authors: Ye
authors: Youfu
authors: Y
authors: Luo
authors: Zhenling
authors: Z
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006505:Hepatitis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000633:toxicity; D010636:Phenols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011621:Pteridines / Q000494:pharmacology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D003208:Concanavalin A; D016207:Cytokines; D008934:Mitogens; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011621:Pteridines; C539252:3-(2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl)phenol; C421683:Pik3cd protein, mouse