Abstract
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.
Highlights
Alpha-melanocyte-simulating hormone (α-MSH) is an endogenous tridecapeptide neurohormone derived from proopiomelanocortin (POMC), which participates in modulating cutaneous inflammatory and immune responses in normal human keratinocytes, langerhans cells, melanocytes and dermal fibroblasts [1, 2]. α-MSH exerts multiple biological effects on PLOS ONE | DOI:10.1371/journal.pone.0136887 August 26, 2015Alpha-MSH Effect on TLR2-Mediated Inflammatory Responses in HK Cells regulating cell proliferation, melanogenesis, immunomodulation, and cytoprotection in the skin through melanocortin 1 receptor (MC1R), a specific G-coupled protein receptor [3]
To analyze α-MSH effect on TLR2 expression induced by a major staphylococcal cell wall component, HK cells were treated with 10 μg/ml S. aureus-derived lipoteichoic acid (LTA) in the presence or absence of 10−7 M α-MSH
Human IRAK-M expression is restricted to monocytes and macrophages [26, 35], there is no known information about the regulatory effect of α-MSH on TLR2-mediated inflammatory responses in S. aureus LTA-induced keratinocytes
Summary
Alpha-melanocyte-simulating hormone (α-MSH) is an endogenous tridecapeptide neurohormone derived from proopiomelanocortin (POMC), which participates in modulating cutaneous inflammatory and immune responses in normal human keratinocytes, langerhans cells, melanocytes and dermal fibroblasts [1, 2]. Alpha-MSH Effect on TLR2-Mediated Inflammatory Responses in HK Cells regulating cell proliferation, melanogenesis, immunomodulation, and cytoprotection in the skin through melanocortin 1 receptor (MC1R), a specific G-coupled protein receptor [3]. It was previously reported that α-MSH prevents TNFα-induced NF-κB transactivation through MC1R in human dermal fibroblast cells [4]. Α-MSH has been reported to be a potent inhibitor of acute and chronic inflammation in a number of tissues [6], and it inhibits the functional expression of immunoregulatory and pro-inflammatory cytokines such as IL-2, IFN-γ, TNFα, IL-6, and ICAM-1 [7]. Subcutaneous, or intravenous administration of α-MSH inhibits contact hypersensitivity (CHS) via up-regulation of IL-10 [9]
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