The Alpha-Melanocyte-Stimulating Hormone Suppresses TLR2-Mediated Functional Responses through IRAK-M in Normal Human Keratinocytes

PLoS One. 2015 Aug 26;10(8):e0136887. doi: 10.1371/journal.pone.0136887. eCollection 2015.


Alpha-melanocyte stimulating hormone (α-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 α-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of α-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs). α-MSH pretreatment down-regulated the Staphylococcus aureus LTA-induced expression of both TLR2 and IL-8 as well as NF-κB nuclear translocation in HK cells. The inhibitory effect of α-MSH was blocked by agouti signaling protein (ASP), an α-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 α-MSH suppressive effect on IL-8 production and NF-κB transactivation was inhibited by IRAK-M siRNA transfection in HK cells. These results indicate that α-MSH is capable of suppressing keratinocyte TLR2-mediated inflammatory responses induced by S. aureus-LTA, thus demonstrating another novel immunomodulatory activity of α-MSH in normal human keratinocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Silencing
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / deficiency
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism*
  • Keratinocytes / microbiology
  • Lipopolysaccharides / biosynthesis
  • Lipopolysaccharides / pharmacology
  • NF-kappa B / metabolism
  • RNA, Small Interfering / genetics
  • Staphylococcus aureus / metabolism
  • Teichoic Acids / biosynthesis
  • Teichoic Acids / pharmacology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • alpha-MSH / pharmacology*


  • Interleukin-8
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Small Interfering
  • TLR2 protein, human
  • Teichoic Acids
  • Toll-Like Receptor 2
  • lipoteichoic acid
  • alpha-MSH
  • IRAK3 protein, human
  • Interleukin-1 Receptor-Associated Kinases