Fetal human keratinocytes produce large amounts of antimicrobial peptides: involvement of histone-methylation processes.
Antimicrobial peptides (AMPs), an important part of the innate immune system, are crucial for defense against invading microorganisms. Whereas AMPs have been extensively studied in adult skin, little is known about the impact of AMPs in the developing human skin. We therefore compared the expression and regulation of AMPs in fetal, neonatal, and adult keratinocytes (KCs) in vitro. The constitutive expression of human β-defensin-2 (HBD-2), HBD-3, S100 protein family members, and cathelicidin was significantly higher in KCs from fetal skin than in KCs from postnatal skin. The capacity to further increase AMP production was comparable between prenatal and postnatal KCs. Analysis of skin equivalents (SEs) revealed a strong constitutive expression of S100 proteins in fetal but not in neonatal and adult SEs. The elevated AMP levels correlated with reduced H3K27me3 (tri-methyl-lysine 27 on histone H3) levels and increased expression of the histone demethylase JMJD3. Knockdown of JMJD3 in fetal KCs elevated H3K27me3 levels and significantly downregulated the expression of HBD-3, S100A7, S100A8, S100A9, and cathelicidin. Our data indicate a crucial contribution of histone modifications in the regulation of AMP expression in the skin during ontogeny. The elevated AMP expression in prenatal skin might represent an essential defense strategy of the unborn.
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Maria
M
Gschwandtner
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Department of Dermatology, Peking University First Hospital, Beijing, China.
Shaomin
S
Zhong
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Antonia
A
Tschachler
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Veronika
V
Mlitz
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Susanne
S
Karner
Laboratory of Cellular and Molecular Immunobiology of the Skin, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Adelheid
A
Elbe-Bürger
Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: michael.mildner@meduniwien.ac.at.
Michael
M
Mildner
D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D002478:Cells, Cultured; D005333:Fetus / Q000276:immunology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology; D015603:Keratinocytes / Q000276:immunology*; D008745:Methylation; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics; D051193:Toll-Like Receptors / Q000502:physiology; D023083:beta-Defensins / Q000096:biosynthesis / Q000235:genetics
D023181:Antimicrobial Cationic Peptides; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D006657:Histones; D009418:S100 Proteins; D051193:Toll-Like Receptors; D023083:beta-Defensins; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human