New Insights into the Functions of α‐MSH and Related Peptides in the Immune System

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Abstract
There is a substantial body of evidence that the tridecapeptide α‐melanocyte‐stimulating hormone (α‐MSH) functions as a mediator of immunity and inflammation. The immunomodulating capacity of α‐MSH is primarily because of its effects on melanocortin receptor (MC‐1R)‐expressing monocytes, macrophages, and dendritic cells (DCs). α‐MSH down‐regulates the production of proinflammatory and immunomodulating cytokines (IL‐1, IL‐6, TNF‐α, IL‐2, IFN‐γ, 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 α‐MSH. At the molecular level, these effects of α‐MSH are mediated via the inhibition of the activation of transcription factors such as NFκB. Not only α‐MSH but also its C‐terminal tripeptide (α‐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 α‐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 vivo transfer experiments. Treatment of naive mice with bone marrow‐derived immature haptenized and α‐MSH‐pulsed DCs resulted in a significant inhibition of CHS. Furthermore, tolerance induction was found to be mediated by the generation of CTLA4+ and IL‐10‐producing T lymphocytes. The potent capacity of α‐MSH to modulate the function of antigen‐presenting cells (APCs) has been further supported in another experimental approach. In vitro, by activating APCs, α‐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 α‐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 α‐MSH treatment. Therefore, therapeutic application of α‐MSH or related peptides (KPVs) as well as α‐MSH/KPV‐pulsed DCs may be a useful approach for the treatment of inflammatory, autoimmune, and allergic diseases in the future.