Protective effect of Go6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice

Protein kinase D (PKD) is a newly described serine/threonine protein kinase that plays a pivotal role in inflammatory response. In the present study, we examined the protective effect of Go6976, a PKD inhibitor, on lipopolysaccharide (LPS) and d-galactosamine (d-GalN)-induced acute liver injury in mice. Mice were pretreated intraperitoneally with Go6976 30 min before LPS/d-GalN administration . The mortality and degree of hepatic injury was subsequently assessed. The results indicated that LPS/d-GalN administration markedly induced hepatic PKD activation, lethality and liver injury, while pretreatment of the PKD inhibitor Go6976 significantly inhibited LPS-induced PKD activation, improved the survival of LPS/d-GalN-administered mice and attenuated LPS/d-GalN-induced liver injury, as evidenced by reduced levels of serum aminotransferases as well as reduced histopathological changes. In addition, the protective effects of Go6976 were paralleled by suppressed activation of mitogen-activated protein kinases (MAPKs), decreased expression of tumor necrosis factor-alpha (TNF-alpha) and adhesion molecules, and reduced apoptosis and myeloperoxidase (MPO) activity in liver. Our experimental data indicated that Go6976, a PKD inhibitor, could effectively prevent LPS/d-GalN-induced acute liver injury by inhibition of MAPKs activation to reduce TNF-alpha production. This suggests the potential pharmacological value of PKD inhibitors in the intervention of inflammation-based liver diseases.