(from the application): Alpha-MSH acts as a potent immunomodulator of cutaneous inflammation. This neuropeptide is produced in the skin and has been shown to mediate both immunostimulating and immunosuppressive activities. The general hypothesis to be tested in this application is that alpha-MSH may be an important modulator of dermal microvascular endothelial cell (DMEC) inflammatory responses such as chemokine production and cellular adhesion molecule expression which are critical initiating events in the cascade of cutaneous inflammation. It remains to be determined if alpha-MSH upregulates or suppresses DMEC mediated inflammation. The role of endothelial cells in alpha-MSH mediated cutaneous inflammation will be tested in the following specific aims which utilize both an in vitro and in vivo model system, employing cultured HDMEC and mice possessing either full wild type or attenuated response capabilities specific for the distinctive pathway of alpha-MSH initiated response under investigation.
Specific Aim #1 : To determine the effect of alpha-MSH on HDMEC chemokine production. Studies designed in this specific aim are designed to examine the ability of alpha-MSH to modulate the production of HDMEC C-X-C and C-C chemokines which may act as leukocyte chemotactic agents in inflammatory skin disease.
Specific Aim #2 : To determine the effect of alpha-MSH on HDMEC cellular adhesion molecule expression and leukocyte adhesion. Studies designed in this aim will test the ability of alpha-MSH to modulate the expression of HDMEC cellular adhesion molecules ICAM-1, VCAM-1, and E-selectin. In parallel, functional studies will be carried out measuring the effect of alpha-MSH on leukocyte adhesion to HDMEC.
Specific Aim #3 : To determine the effect of alpha-MSH in DMEC mediated responses in inflammatory skin disease. Studies designed to test this aim will address the contribution of alpha-MSH-dependent activation of DMEC in the pathogenesis of inflammation generated in three distinct murine models of common cutaneous inflammatory diseases: allergic contact dermatitis, irritant dermatitis, and acute photodermatitis in wild type and genetically altered animals. The results of these investigations will lead to a better understanding of the complex mechanisms involved in endothelial cell mediated inflammation of the skin and to improved treatment strategies for cutaneous inflammatory diseases.
