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Endocrinology Vol. 144, No. 1 360-370
Copyright © 2003 by The Endocrine Society

ARTICLE

{alpha}-Melanocyte Stimulating Hormone Prevents Lipopolysaccharide-Induced Vasculitis by Down-Regulating Endothelial Cell Adhesion Molecule Expression

T. E. Scholzen, C. Sunderkötter, D.-H. Kalden, T. Brzoska, M. Fastrich, T. Fisbeck, C. A. Armstrong, J. C. Ansel and T. A. Luger

Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin (T.E.S., D.-H.K., T.B., M.F., T.F., T.A.L.), Institute of Experimental Dermatology (C.S.), Department of Dermatology (C.S., T.A.L.), University of Münster, 48149 Münster, Germany; and Department of Dermatology (C.A.A., J.C.A.), Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Dr. Thomas Scholzen, Ph.D., University of Münster, Department of Dermatology, Ludwig Boltzmann Institute for Cell and Immunobiology of the Skin, Von-Esmarch-Strasse 58, 48149 Münster, Germany. E-mail: thoscho{at}uni-muenster.de.

The neuroendocrine hormone {alpha}-melanocyte stimulating hormone (MSH) has profound antiinflammatory and immunomodulating properties. Here we have examined the possibility that {alpha}-MSH may interfere with the expression and function of cell adhesion molecules (CAMs) expressed by human dermal microvascular endothelial cells (HDMECs) in response to lipopolysaccharide (LPS) or TNF{alpha} in vitro and in vivo. In HDMEC, {alpha}-MSH (10-8/10-12 M) profoundly reduced the mRNA and protein expression of E-selectin, vascular CAM (VCAM)-1, and intercellular CAM (ICAM)-1 induced by LPS or TNF{alpha} as determined by semiquantitative RT-PCR, ELISA, and fluorescence-activated cell sorter analysis. In addition, {alpha}-MSH significantly impaired the LPS-induced ICAM-1 and VCAM-1-mediated adhesion of lymphocytes to HDMEC monolayer in a functional adhesion assay. Likewise, {alpha}-MSH effectively inhibited the transcription factor nuclear factor-{kappa}B activation in HDMEC, which is required for CAM gene expression. Importantly in vivo, in murine LPS-induced cutaneous vasculitis (local Shwartzman reaction), a single ip injection of {alpha}-MSH significantly suppressed the deleterious vascular damage and hemorrhage by inhibiting the sustained expression of vascular E-selectin and VCAM-1. This persistent expression has been implicated in the dysregulation of diapedesis and activation of leukocytes, which subsequently leads to hemorrhagic vascular damage. Our findings indicate that {alpha}-MSH may have an important therapeutical potential for the treatment of vasculitis, sepsis, and inflammatory diseases.




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