Vitamin D, Resveratrol, and Control of LCE3 Genes with Implications for Psoriasis

Abstract

Psoriasis (Psx) is a chronic inflammatory skin disease with abnormal keratinocyte proliferation and differentiation. One genetic risk factor for psoriasis (denoted PSORS4) is a deletion of LCE3B and LCE3C genes encoding structural proteins in terminally differentiated keratinocytes. Analogs of the hormonal form of vitamin D, 1,25‐dihydroxyvitamin D3 (1,25D) are routinely used to treat Psx, a skin disease that affects over 7 million patients in the US. However, this therapy, even when combined with an anti‐inflammatory (e.g., betamethasone), is ineffective in some patients, particularly those with a severe disease phenotype, underscoring the need for better agents. Further, the mechanism of action of vitamin D analogs is not understood, although their ability to reduce proliferation and promote differentiation of psoriatic keratinocytes is both valued in therapy and is complementary to anti‐inflammatory agents. Given that 1,25D acts via the vitamin D receptor (VDR) to regulate gene expression, this project is focused on elucidating expression alterations in psoriasisrelevant genes mediated by the 1,25D‐liganded VDR in human keratinocytes. Whereas VDR activity is increased when bound to 1,25D, less is known about the ability of other nutritionallyderived lipids to act on VDR. The current study is designed to: 1) evaluate resveratrol, an antioxidant found in the skin of red grapes, as an effector of VDR signaling and potent activator of LCE gene transcription in human keratinocytes, and 2) determine whether resveratrol acts synergistically with 1,25D to regulate the expression of LCE3 genes, with the potential to boost skin repair and ameliorate the symptoms of psoriasis.