Neural regulation of endothelial cell-mediated inflammation

There is increasing evidence that the cutaneous neurosensory system can dir ectly modulate inflammatory responses in the skin by the release of neurope ptides such as substance P (SP), Dermal microvascular endothelial cell (DME C) cellular adhesion molecule (CAM) expression plays a key role in directin g leukocyte trafficking during cutaneous inflammatory responses. In recent studies, our laboratory examined the direct effect of SP on DMEC CAM expres sion and function in vitro and in vivo, Our studies indicate that DMEC expr ess high affinity functional receptors for SP. After exposure to SP, DMEC e xpressed significant levels of both intercellular adhesion molecule 1 (ICAM -1) and vascular cell adhesion molecule-1 (VCAM-1), which was accompanied b y increased binding to leukocytes expressing the appropriate integrin count er receptors for these CAM, We then determined the in vivo effect of releas ed neuropeptides on DMEC CAM expression. Our results indicate that the topi cal cutaneous application of the neuropeptide-releasing agent capsaicin res ulted in increased ICAM-1 and VCAM-1 immunostaining of microvascular cells in the skin of human volunteers. Little is known regarding the cellular reg ulatory events by which SP modulates DMEC CAM expression. Our studies indic ate that SP-induced cellular Ca+2 signals led to the activation of the NF-k appaB pathway, resulting in nuclear translocation of p65/p50 heterodimers t hat bind to high-affinity tandem kappaB sites on the VCAM-1 promoter, where as SP activation induced NF-AT activation and ICAM-1 DNA binding. Thus, the se studies further support the role of the cutaneous neurologic system in m odulating inflammatory processes in the skin.