Mitogen-activated protein kinases (MAPK’s) play key roles in inflammatory signaling. Studies by ours and other groups have implicated ERK1/2 and ERK5 in TLR-dependent signaling. We identified novel roles for ERK1/2 and ERK5, in the activation of leukocytes and endothelial cells by bacterial TLR agonists and host inflammatory factors (e.g.:TNF⍺, IL-1β). Our work suggests that ERK1/2 activation plays divergent roles in the inflammatory activation of human endothelial cells versus leukocytes by TLR2 and TLR4 agonists.