The Alpha-Melanocyte-Stimulating Hormone Suppresses Tlr2-Mediated Functional Responses Through Irak-M In Normal Human Keratinocytes

Alpha-melanocyte stimulating hormone (alpha-MSH) is a highly conserved 13-aa neuropeptide derived from pro-opiomelanocortin by post-translational processing, which has been reported to exhibit potent anti-inflammatory activity and a wide range of immunosuppressive activities in the skin. However, the regulatory effect of alpha-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of alpha-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs). alpha-MSH pretreatment down-regulated the Staphylococcus aureus LTA-induced expression of both TLR2 and IL-8 as well as NF-kappa B nuclear translocation in HK cells. The inhibitory effect of alpha-MSH was blocked by agouti signaling protein (ASP), an alpha-MSH receptor-1 antagonist. To investigate the mechanism of this response in more detail, siRNA of IRAK-M, a negative regulator of TLR signaling, was utilized in these studies. The alpha-MSH suppressive effect on IL-8 production and NF-kappa B transactivation was inhibited by IRAK-M siRNA transfection in HK cells. These results indicate that alpha-MSH is capable of suppressing keratinocyte TLR2-mediated inflammatory responses induced by S. aureus-LTA, thus demonstrating another novel immunomodulatory activity of alpha-MSH in normal human keratinocytes.