α-Melanocyte-Stimulating Hormone as a Mediator of Tolerance Induction

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Abstract
There is accumulating evidence for a strong interaction between components of the nervous system and the immune system. Accordingly, specific receptors for neuropeptides were found to be expressed on immunocompetent cells and several neuropeptides were recognized as potent regulators of immune and inflammatory reactions. Among various neuropeptides such as substance P, calcitonin gene-related peptide and others α-melanocyte-stimulating hormone (α-MSH) was found to be produced in the skin. Moreover, melanocortin receptor 1 which is specific for α-MSH and ACTH is expressed in the skin on keratinocytes, dendritic cells, macrophages and endothelial cells. In monocytes, macrophages and dendritic cells α-MSH inhibits the production and activity of immunoregulatory and proinflammatory cytokines such as IL-2, IFNγ and IL-1. It downregulates the expression of costimulatory molecules such as CD86 and CD40 and induces the production of suppressor factors such as the cytokine synthesis inhibitory factor IL-10. On endothelial cells α-MSH is capable of downregulating the LPS-induced expression of adhesion molecules such as vascular cellular adhesion molecules and E-selectin. Moreover, the LPS-induced activation of transcription factors such as NFκB is downregulated by α-MSH. In a mouse model intravenous or topical application of α-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 α-MSH is sufficient for its in vitro and in vivo immunomodulatory effects. These findings indicate that the production of immunosuppressing neuropeptides such as α-MSH by epidermal cells may play an essential role during the pathogenesis of immune and inflammatory reactions in the skin.

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