title: Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells.
abstract: A critical function for skin is that when damaged it must simultaneously identify the nature of the injury, repair barrier function, and limit the intrusion of pathogenic organisms. These needs are carried out through the detection of damage-associated molecular patterns (DAMPs) and a response that includes secretion of cytokines, chemokines, growth factors, and antimicrobial peptides (AMPs). In this study, we analyzed how non-coding double-stranded RNA (dsRNAs) act as a DAMP in the skin and how the human cathelicidin AMP LL-37 might influence growth factor production in response to this DAMP. dsRNA alone significantly increased the expression of multiple growth factors in keratinocytes, endothelial cells, and fibroblasts. Furthermore, RNA sequencing transcriptome analysis found that multiple growth factors increase when cells are exposed to both LL-37 and dsRNA, a condition that mimics normal wounding. Quantitative PCR and/or ELISA validated that growth factors expressed by keratinocytes in these conditions included, but were not limited to, basic fibroblast growth factor (FGF2), heparin-binding EGF-like growth factor (HBEGF), vascular endothelial growth factor C (VEGFC), betacellulin (BTC), EGF, epiregulin (EREG), and other members of the transforming growth factor β superfamily. These results identify a novel role for DAMPs and AMPs in the stimulation of repair and highlight the complex interactions involved in the wound environment.
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Adase
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Borkowski
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093.
authors.forename: Ling-Juan
authors.initials: LJ
authors.lastname: Zhang
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Williams
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093.
authors.forename: Emi
authors.initials: E
authors.lastname: Sato
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093.
authors.forename: James A
authors.initials: JA
authors.lastname: Sanford
authors.affiliation: From the Department of Dermatology, University of California, San Diego, California 92093 rgallo@ucsd.edu.
authors.forename: Richard L
authors.identifier: 0000-0002-1401-7861
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D023181:Antimicrobial Cationic Peptides; D015153:Blotting, Western; D054804:Cathelicidins / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012330:RNA, Double-Stranded / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D066257:Heparin-binding EGF-like Growth Factor; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D022661:RNA, Untranslated; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D016222:Fibroblast Growth Factor 2
keywords: antimicrobial peptide (AMP); betacellulin; cathelicidin; double-stranded RNA (dsRNA); fibroblast growth factor (FGF); insulin-like growth factor (IGF); keratinocyte; vascular endothelial growth factor (VEGF)