Biopositive Effects of Low-Dose UVB on Epidermis: Coordinate Upregulation of Antimicrobial Peptides and Permeability Barrier Reinforcement

Abstract

Whereas high-dose ultraviolet B (UVB) is detrimental to the epidermal permeability barrier, suberythemal doses of UVB are used to treat atopic dermatitis (AD), which is characterized by defective permeability barrier and antimicrobial function. As epidermal permeability barrier and antimicrobial peptide (AMP) expression are coregulated and interdependent functions, we hypothesized that suberythemal doses of UVB exposure could regulate AMP expression in parallel with permeability barrier function. Hairless mice were exposed to 40 mJ cm(-2) UVB (about 1/2 minimal erythema dose) daily for 1 or 3 days. Twenty-four hours after the last exposure, epidermal barrier function was assessed and skin specimens were taken for western blotting, immunohistochemistry, and quantitative reverse transcription-PCR for mouse beta-defensin (mBD)-2, mBD3 and cathelin-related antimicrobial peptide (CRAMP). mRNA levels of the vitamin D receptor (VDR), 1alpha-hydroxylase and key epidermal lipid synthetic enzymes were also quantified. After 3 days of UVB exposure, acceleration of barrier recovery and augmentation in expression of epidermal differentiation markers (for example, involucrin and filaggrin) occurred in parallel with increased mBD2, mBD3, and CRAMP expression at both the mRNA and protein level. VDR, 1alpha-hydroxylase, and the major epidermal lipid synthetic enzymes were also upregulated. When an inhibitor of 1alpha, 25 dihydroxyvitamin D(3) formation, ketoconazole, was applied immediately after UVB exposure, the cutaneous vitamin D system was inhibited, which in turn blocked epidermal lipid synthesis, AMP expression, and permeability barrier homeostasis, suggesting that the beneficial effect of low-dose UVB depends, at least in part, on activation of the cutaneous vitamin D system. Our results provide new insights into the mechanisms whereby low-dose UVB comprises effective therapy for AD.

An Endoplasmic Reticulum Stress-Initiated Sphingolipid Metabolite, Ceramide-1-Phosphate, Regulates Epithelial Innate Immunity by Stimulating β-Defensin Production

“…Many types of external perturbations, including microbial infections, increase hBD2, hBD3, and CAMP production in epithelial cells (2,5,41), but the mechanisms responsible have not yet been fully characterized. When investigating how these perturbants stimulate AMP production, we recently found that these various unrelated forms of external perturbations induce ER stress, which in turn increases production of Cer and S1P (8).…”

“…To protect the internal milieu from exogenous pathogens, these epithelia upregulate multiple innate immune elements, including several AMP that together provide an effective antimicrobial barrier against these external threats. We and others have demonstrated that AMP production increases following external perturbations, such as UV irradiation, oxidative stress, inflammation, and wounding (2)(3)(4)(5)(6). We also showed that most of these external perturbations induce endoplasmic reticulum (ER) stress, which in turn stimulates production of a major AMP, cathelicidin antimicrobial peptide (CAMP), in epithelial cells/tissues (7).…”

A Novel Role of a Lipid Species, Sphingosine-1-Phosphate, in Epithelial Innate Immunity

“…Prior studies demonstrated that various unrelated external perturbations, including UV B (UVB) irradiation, wounding, and permeability barrier abrogation, induce endoplasmic reticulum (ER) stress (3), which in turn stimulates a set of responses that rescue cells from apoptosis (4). These responses include increased expression of CAMP in epithelial tissues such as mammalian epidermis (5)(6)(7)(8). We showed recently that comparable external perturbations also stimulate CAMP production in epithelial but not myeloid cells, via a novel NF-B-and C/EBP␣-mediated pathway independent of the well-known, vitamin D receptor (VDR)-mediated mechanism (9).…”

Epidermal Barrier: Negative Changes in Atopic Dermatitis and Positive Changes Induced by Short-term Suberythemal Ultraviolet B Irradiation

“…A study on hairless mice exposed to 0.5 MED of UVB irradiation (40 mJ/cm 2 ) daily for 3 days demonstrated positive effects of UVB on epidermis, which, at least in part, is mediated by cutaneous vitamin D 3 activation [59]. There was an upregulation of cutaneous vitamin D 3 system and an increase in the mRNA levels for the epidermal lipid synthetic enzymes, HMG-CoA, Fatty Acid Synthase (FAS), and SPT [59].…”