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

An increasing number of studies have suggested that phosphoinositide 3-kinase-gamma (PI3K gamma) and PI3K delta 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 PI3K delta/gamma inhibition on hepatic injury in a murine model of hepatitis induced by concanavalin A (ConA). It was demonstrated that the pharmacological ;inhibition of PI3K delta/gamma by TG100-115 did not prevent liver damage following ConA challenge. Furthermore, the PI3K delta/gamma 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 PI3K delta/gamma inhibitors as therapeutic agents, particularly for the treatment of human hepatitis.