Lipopolysaccharide induces Jun N-terminal kinase activation in macrophagesby a novel Cdc42/Rac-independent pathway involving sequential activation of protein kinase C zeta and phosphatidylcholine-dependent phospholipase C

The activation of kinases of the mitogen-activated protein kinase superfami ly initiated by lipopolysaccharide (LPS) plays an important role in transdu cing inflammatory signals. The pathway leading to the induction of stress-a ctivated protein kinases in macrophages stimulated with LPS was investigate d. The activation of Jun N-terminal kinases (JNK) by LPS is herbimycin sens itive. Using specific inhibitors, it was shown that the pathway involves th e activation of phosphoinositide 3-kinase (PI 3-K), However, in contrast to previous reports, the small GTPases Cdc42 and Pac are not required downstr eam of PI 3-K for JNK activation. Instead, the phosphoinositides produced b y PI 3-K stimulate protein kinase c (PKC) zeta activation through PDK1, In turn, activation of this atypical PKC leads to the stimulation of phosphati dylcholine phospholipase C (PC-PLC) and acidic sphingomyelinase (ASMase), I t is therefore proposed that PKC zeta; regulates the PC-PLC/ASMase pathway, and It Is hypothesized that the resultant ceramide accumulation mediates t he activation of the SEK/JNK module by LPS. (Blood. 2000;96:2592-2598) (C) 2000 by The American Society of Hematology.