alpha-Melanocyte-stimulating hormone (alpha-MSH), an anti-inflammatory and immunomodulatory neuropeptide, has been shown to be effective in the experimental treatment of autoimmune diseases and allograft rejection. However, its regulatory mechanism is still unclear. Mature dendritic cells (DCs) are pivotal initiators of immune response and inflammation. We hypothesized that the regulatory role of alpha-MSH in DC maturation would contribute to the effects of alpha-MSH in immune-response-mediated disease models. It was found that alpha-MSH inhibited tumor necrosis factor-alpha (TNF-alpha)-induced maturation of human peripheral-monocyte-derived DCs (MoDCs), both phenotypically and functionally. This occurred through the down-regulation of the expression of co-stimulatory molecules CD83 and CD86, the production of IL-12, the promotion of IL-10 secretion, and the MoDC phagocytic activity, suggesting that the inhibition of DC maturation by alpha-MSH could contribute to the anti-inflammatory effect of this neuropeptide. Furthermore, increased expression of annexin A1 (ANXA1) was found to be responsible for the alpha-MSH inhibiting effect on TNF-alpha-induced MoDC maturation, which could be abolished by the treatment of MoDCs with specific, small interfering RNAs targeting ANXA1 (ANXA1-siRNA), suggesting that alpha-MSH-induced ANXA1 mediates the inhibition. Therefore, alpha-MSH inhibits TNF-alpha-induced maturation of human DCs through alpha-MSH-up-regulated ANXA1, suggesting that inhibition of the maturation of DCs by alpha-MSH could mediate the anti-inflammatory effect of the neuropeptide. Furthermore, ANXA1 could be identified as a new therapeutic drug target based on the role of DCs in immune-mediated inflammatory diseases.
[1]Second Mil Med Univ, Inst Immunol, Shanghai 200433, Peoples R China.
[2]Second Mil Med Univ, Natl Key Lab Med Immunol, Shanghai 200433, Peoples R China.
[3]Fudan Univ, Sch Life Sci, Inst Genet, State Key Lab Genet Engn, Shanghai 200433, Peoples R China.
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