1. ¹Division of Dermatology, University of California, San Diego and VA San Diego Healthcare System, San Diego, California, USA
2. ²Department of Dermatology, Ludwig-Maximilians-University, Munich, Germany
3. ³Department of Medicine, Endocrine Unit, Veterans Affairs Medical Centre, University of California, San Francisco, California, USA
4. ⁴School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
5. ⁵Medicinal Chemistry, Bayer Schering Pharma AG, Berlin, Germany
6. ⁶Therapeutic Research Group Inflammation & Immunology, Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany

Correspondence: Dr Richard L. Gallo, 3350 La Jolla Village Drive, Mail Code 151, San Diego, California 92161, USA. E-mail: rgallo@ucsd.edu

Received 12 June 2007; Revised 30 July 2007; Accepted 13 August 2007; Published online 18 October 2007.

Abstract

Hormonally active vitamin D₃—1,25-dihydroxyvitamin D₃ (1,25D3)—acts as a signaling molecule in cutaneous immunity by increasing pattern recognition through Toll-like receptor-2 (TLR2), and increasing the expression and function of antimicrobial peptides. Here we show that the actions of 1,25D3 on keratinocyte innate immune responses are influenced by histone acetylation and require the steroid receptor coactivator 3 (SRC3), which mediates inherent histone acetyltransferase (HAT) activity. SRC3 was detected in the suprabasal and granular layer of the skin, similar to cathelicidin expression. HAT activity was important to keratinocyte cathelicidin expression as the combination of histone deacetylase inhibitors (HDACi) (butyrate or trichostatin A) and 1,25D3 increased cathelicidin and CD14 expression and enhanced the antimicrobial function of keratinocytes against Staphylococcus aureus. This treatment, or activation of TLR2, also directly increased acetylation of histone 4. Small interfering RNA silencing of the vitamin D receptor or SRC3 blocked the induction of cathelicidin and CD14 by 1,25D3. HDACi could not reverse this effect or influence cathelicidin in the absence of 1,25D3, suggesting that both are necessary for function. These studies demonstrate that the epigenetic control of gene transcription by histone acetylation is important for 1,25D3-regulated antimicrobial and TLR function of keratinocytes, essential elements of the innate immune response of the skin.