alpha-melanocyte-stimulating hormone as a mediator of tolerance induction

There is accumulating evidence for a strong interaction between components of the nervous system and the immune system. Accordingly, specific receptor s for neuropeptides were found to be expressed on immunocompetent cells and several neuropeptides were recognized as potent regulators of immune and i nflammatory reactions. Among various neuropeptides such as substance P, cal citonin gene-related peptide and others alpha-melanocyte-stimulating hormon e (alpha-MSH) was found to be produced in the skin, Moreover, melanocortin receptor 1 which is specific for alpha-MSH and ACTH is expressed in the ski n on keratinocytes, dendritic cells, macrophages and endothelial cells. In monocytes, macrophages and dendritic cells alpha-MSH inhibits the productio n and activity of immunoregulatory and proinflammatory cytokines such as IL -2, IFN gamma and IL-l, it downregulates the expression of costimulatory mo lecules such as CD86 and CD40 and induces the production of suppressor fact ors such as the cytokine synthesis inhibitory factor IL-10. On endothelial cells alpha-MSH is capable of downregulating the LPS-induced expression of adhesion molecules such as vascular cellular adhesion molecules and E-selec tin. Moreover, the LPS-induced activation of transcription factors such as NF kappa B is downregulated by alpha-MSH. In a mouse model intravenous or t opical application of alpha-MSH was found to inhibit the induction as well as the effector phase of a contact hypersensitivity reaction and to induce hapten-specific tolerance. Moreover, there is evidence that the N-terminal tripeptide of alpha-MSH is sufficient for its in vitro and in vivo immunomo dulatory effects. These findings indicate that the production of immunosupp ressing neuropeptides such as alpha-MSH by epidermal cells may play an esse ntial role during the pathogenesis of immune and inflammatory reactions in the skin. Copyright (C) 2000 S. Karger AG, Basel.