Novel Pkc Signaling Is Required for Lps-Induced Soluble Flt-1 Expression in Macrophages

In vitro activation of macrophages by LPS induces rapid release of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 receptor (sFlt-1), which are thought to be the effectors to cause sepsis. However, the signal pathway that controls the VEGF and sFlt-1 expressions in LPS-activated macrophages remains unclear. In this study, we demonstrated that phosphorylation of protein kinase C (PKC) VEGF and sFlt-1 signaling pathway of LPS- activated macrophages. PKC is a family of serine-threonine kinases, which are classified into three major groups based on homology and cofactor requirements: conventional PKCs, novel PKCs , and atypical PKCs. In the murine RAW264.7 cells, as well as in primary human monocytes/macrophages, pretreatment with a general PKC inhibitor GF 109203X or with a novel PKC inactive form of PKC LPS-induced sFlt-1 expression and augmented LPSinduced VEGF expression at the protein and the transcription levels. In contrast, Go 6976 , an inhibitor for the conventional PKCs, or myristoylated PKC pseudosubstrate peptide, an inhibitor for the atypical PKCs, failed to exert the same effects. These data suggest that PKC sFlt-1 expression and serves as a negative mediator in LPS-induced VEGF expression in macrophages. A novel strategy controlling the LPS-induced PKC pathways, especially the PKC developed based on this study