Hepatocyte growth factor modulates activation and antigen-presenting cell 
function of dendritic cells. However, the molecular basis for immunoregulation 
of dendritic cells by hepatocyte growth factor is undefined. In the current 
study, we demonstrate that hepatocyte growth factor exhibits inhibitory effect 
on dendritic cell activation by blocking IκB kinase activity and subsequent 
nuclear factor-κB activation. Inhibition of IκB kinase is mediated by hepatocyte 
growth factor-induced activation of c-Src. Proximal signaling events induced in 
dendritic cells by hepatocyte growth factor include a physical association of 
c-Src with the hepatocyte growth factor receptor c-MET and concomitant 
activation of c-Src. Activation of c-Src in turn establishes a complex 
consisting of phosphatidylinositol 3-kinase and c-MET, and promotes downstream 
activation of the phosphatidylinositol 3-kinase/AKT pathway and mammalian target 
of rapamycin. Blocking activation of c-Src, phosphatidylinositol 3-kinase and 
mammalian target of rapamycin prevents hepatocyte growth factor-induced 
inhibition of IκB kinase, nuclear factor-κB and dendritic cell activation. 
Notably, hepatocyte growth factor-stimulated c-Src activation results in 
induction of phosphatidylinositol 3-kinase complexes p85α/p110α and p85α/p110δ, 
which is required for activation of mammalian target of rapamycin, and 
consequent inhibition of IκB kinase and nuclear factor-κB activation. Our 
findings, for the first time, have identified the c-Src-phosphatidylinositol 
3-kinase-AKT-mammalian target of rapamycin pathway that plays a pivotal role in 
mediating the inhibitory effects of hepatocyte growth factor on dendritic cell 
activation by blocking nuclear factor-κB signaling.