New Insights into the Functions of ?-MSH and Related Peptides in the Immune System

There is a substantial body of evidence that the tridecapeptide ?-melanocyte-stimulating hormone (?-MSH) functions as a mediator of immunity and inflammation. The immunomodulating capacity of ?-MSH is primarily because of its effects on melanocortin receptor (MC-1R)-expressing monocytes, macrophages, and dendritic cells (DCs). ?-MSH down-regulates the production of proinflammatory and immunomodulating cytokines (IL-1, IL-6, TNF-?, IL-2, IFN-?, IL-4, IL-13) as well as the expression of costimulatory molecules (CD86, CD40, ICAM-1) on antigen-presenting DCs. In contrast, the production of the cytokine synthesis inhibitor IL-10 is up-regulated by ?-MSH. At the molecular level, these effects of ?-MSH are mediated via the inhibition of the activation of transcription factors such as NF?B. Not only ?-MSH but also its C-terminal tripeptide (?-MSH 11-13, KPV) was able to bind to MC-1R and to modulate the function of APCs. In vivo, using a mouse model of contact hypersensitivity (CHS) systemic and topical application of ?-MSH or KPV inhibited the sensitization and the elicitation phase of CHS and was able to induce hapten-specific tolerance. To investigate the underlying mechanisms of tolerance induction, we have performed in vivotransfer experiments. Treatment of naive mice with bone marrow-derived immature haptenized and ?-MSH-pulsed DCs resulted in a significant inhibition of CHS. Furthermore, tolerance induction was found to be mediated by the generation of CTLA4and IL-10-producing T lymphocytes. The potent capacity of ?-MSH to modulate the function of antigen-presenting cells (APCs) has been further supported in another experimental approach. In vitro, by activating APCs, ?-MSH has been shown to modulate IgE production by IL-4 and anti-CD40 stimulated B lymphocytes. Moreover, in a murine model of allergic airway inflammation, systemic treatment with ?-MSH resulted in a significant reduction of allergen-specific IgE production, eosinophil influx, and IL-4 production. These effects were mediated via IL-10 production, because IL-10 knockout mice were resistant to ?-MSH treatment. Therefore, therapeutic application of ?-MSH or related peptides (KPVs) as well as ?-MSHKPV-pulsed DCs may be a useful approach for the treatment of inflammatory, autoimmune, and allergic diseases in the future.