Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4) in keratinocytes is inhibited by retinoic acid.
Human skin is able to mount a fast response against invading harmful bacteria through the rapid production of inducible peptide antibiotics such as the human beta-defensins (hBD). To gain more insight into the role and regulation of inducible beta-defensins in the innate immunity of human skin, we investigated whether gene induction of the human beta-defensins hBD-1, -2, -3, and -4 in keratinocytes is regulated in a similar manner. Therefore, we performed a comparative study of gene expression of these four hBD in primary cultured keratinocytes using real-time PCR. A basal mRNA expression was observed for all four hBD in primary keratinocytes, which strongly increased for hBD-2, -3, and -4 during Ca(2+)-induced differentiation of the keratinocytes. This effect was completely abolished when the keratinocytes were pre-treated with all-trans-retinoic acid (RA). Furthermore, the differential induction of hBD-2, -3, and -4 gene expression in keratinocytes by proinflammatory cytokines, phorbol-myristate-acetate (PMA), and bacteria was inhibited by more than 90% when the keratinocytes were pre-incubated with RA. Inhibition of IL-1beta-mediated hBD-2 induction through RA was further confirmed by gene reporter assays and western-blot analysis. We conclude that RA is a potent inhibitor of beta-defensin induction in keratinocytes and might downregulate the inducible innate chemical defense system of human skin.
Clinical Research Unit, Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse7, D-24105 Kiel, Germany. jharder@dermatology.uni-kiel.de
Jürgen
J
Harder
Ulf
U
Meyer-Hoffert
Kai
K
Wehkamp
Lars
L
Schwichtenberg
Jens-Michael
JM
Schröder
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D011552:Pseudomonas Infections / Q000503:physiopathology; D011550:Pseudomonas aeruginosa; D012333:RNA, Messenger / Q000032:analysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D023083:beta-Defensins / Q000235:genetics*
D000970:Antineoplastic Agents; D002273:Carcinogens; C406407:DEFB1 protein, human; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D014212:Tretinoin; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium