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IL-17A Enhances Vitamin D₃-Induced Expression of Cathelicidin Antimicrobial Peptide in Human Keratinocytes¹

Mark Peric^*, Sarah Koglin^*, Song-Min Kim^*, Shin Morizane, Robert Besch^*, Jörg C. Prinz^*, Thomas Ruzicka^*, Richard L. Gallo and Jürgen Schauber^2,*

^* Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany; and Division of Dermatology, University of California, and Veterans Affairs San Diego Healthcare System, San Diego, CA 92161

Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D₃ (1,25D₃). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D₃. At the same time, coincubation with 1,25D₃ blocked induction of human β-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and cathelicidin. Both, 1,25D₃ and IL-17A signaled cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases cathelicidin through a vitamin D₃-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Emmy Noether Programm; Scha 979/3-1) and the Friedrich Baur Stiftung.

² Address correspondence and reprint requests to Dr. Jürgen Schauber, Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians-Universität München, Frauenlobstrasse 9-11, 80337 München, Germany. E-mail address: juergen.schauber{at}med.uni-muenchen.de

³ Abbreviations used in this paper: pDC, plasmacytoid dendritic cell; CAMP, cathelicidin antimicrobial peptide; HBD2, human β-defensin 2; 1,25D₃, 1,25-dihydroxyvitamin D₃; NHEK, normal human epidermal keratinocyte; VDR, vitamin D receptor; siRNA, small interfering RNA; ActD, actinomycin D.

⁴ The online version of this article contains supplemental material.

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