Abstract

α‐Melanocyte‐stimulating hormone (α‐MSH) exerts numerous immunomodulatory and anti‐inflammatory activities, which at least partly are mediated through the melanocortin receptor‐1 (MC‐1R), expressed on monocytes, dermal fibroblasts, dendritic cells (DCs), endothelial, and epithelial cells. Accordingly, α‐MSH downregulates the production of proinflammatory cytokines and the expression of costimulatory molecules on antigen‐presenting cells (APCs) via inhibiting the activation of transcription factors such as NF‐κB, while upregulating the production of suppressor factors such as IL‐10. Besides α‐MSH, its C‐terminal‐tripeptide KPV and the IL‐1β‐derived tripeptide KPT are capable of modulating APC functions. Using a mouse model of contact hypersensitivity (CHS), systemic and epicutaneous application of α‐MSH, KPV, or KPT inhibited CHS induction and induced hapten‐specific tolerance. However, using MC‐1R‐deficient mice (MC‐1Re/e), tolerance induction was found to be independent of MC‐1R expression. To further investigate the mechanisms responsible for tolerance induction, adoptive transfer experiments were performed. α‐MSH‐treated haptenized DCs inhibited CHS and induced hapten‐specific tolerance, via induction of regulatory T lymphocytes (T reg ). In contrast, using a murine model of intestinal inflammation [Dextransulfate (DSS)‐induced colitis], the expression of a functional MC‐1R was found to be crucial for α‐MSH to exert its anti‐inflammatory activity; in wt mice, weight loss was reduced and the survival rate significantly was improved upon treatment with α‐MSH or KPV. However, DSS colitis was significantly aggravated in MC1‐Re/e mice, resulting in the death of all animals. Bone marrow transplantation from wt mice did not alter the course of inflammation, indicating that MC‐1R expression on non‐hematopoietic cells is crucial for host defense. These findings further support the therapeutic potential of α‐MSH‐related peptides for the treatment of inflammatory, autoimmun...