ABSTRACT: Irradiation of the skin with ultraviolet light (UV) results in profound alterations of both local and systemic immune responses. These effects are largely mediated by soluble mediators released from epidermal cells in response to UV. It is well known that keratinocytes release increased amounts of cytokines upon UV-irradiation. UV-light also induces the release of the proopiomelanocortin (POMC)-derived peptide, α-melanocyte-stimulating hormone (αMSH), from keratinocytes, and upregulates the expression of POMC mRNA. αMSH exerts a variety of immunomodulating and antiinflammatory effects, mainly by virtue of its capacity to alter the function of antigen presenting cells and vascular endothelial cells. Within an in vivo mouse-model, both intravenous and topical application of αMSH resulted in inhibiting the induction, eliciting a contact hypersensitivity reaction, and inducing hapten-specific tolerance. These findings indicate that αMSH, released in the epidermis after UV irradiation, may contribute to UV-mediated immunosuppression. The therapeutic application of αMSH or αMSH-derived peptides may prove to be a useful approach for treating inflammatory skin diseases.