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Immunomodulatory effects of synthetic peptide IDR-1018 in human keratinocytes Wong, Lisa Catherine

Abstract

The diverse immunomodulatory properties of naturally occurring host defence peptides have gained prominence over the past decade. There is large interest in creating small synthetic peptides with similar or enhanced immunomodulatory activities. The epithelia are vital components of the human innate immune system, offering protection against potential pathogens by acting as a physical barrier and actively participating in the immune response. The aim of this study was to examine the direct effects of synthetic host defence peptides on the immune response in keratinocytes, the primary cell type in skin, in the context of wound healing, and to evaluate their ability to modulate the keratinocyte immune response in the presence of other immune mediators. The synthetic peptides HHC-36 and IDR-1018 were shown to have a positive effect on keratinocyte proliferation and caused a dose-dependent induction of IL-6 and IL-8. Neither peptide was able to influence keratinocyte migration on its own. The immunomodulatory effects of IDR-1018 in human keratinocytes were further investigated by co-stimulating cells with IDR-1018 in the presence of immune mediators or TLR agonists. Co-treatment of keratinocytes with IDR-1018 and either the TLR3 agonist poly(I:C) or IL-1β resulted in a synergistic induction of IL-8. This synergy could be seen transcriptionally 8 hours post-stimulation and was associated with increased levels of phosphorylated CREB. Synergistic IL-8 induction was not observed when IDR-1018 was given with Pam3CSK4, flagellin or GM-CSF. Pre-treatment of keratinocytes with inhibitors of p38 MAPK, NF-κB or Src-family kinases suppressed the IDR-1018-induced synergistic IL-8 production in the presence of poly(I:C) or IL-1β. PKC was shown to play a role in the synergy induced by IDR-1018 and IL-1β, but not poly(I:C). The results of this study offer insights into the immunomodulatory properties needed to effectively enhance the protective abilities of the skin, and highlight the complexity of the mechanism of action of IDR-1018.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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