Regulatory effects of 1,25-dihydroxyvitamin D₃ and a novel vitamin D₃ analogue MC903 on secretion of interleukin-1 alpha (IL-1α) and IL-8 by normal human keratinocytes and a human squamous cell carcinoma cell line (HSC-1)

Pro-inflammatory cytokines mediate their biological functions after they are secreted or released from intracellular to extracellular milieu. Keratinocytes have proven to be able to produce various cytokines including IL-1 and IL-8. Dysregulations of IL-1 and IL-8 were found in psoriatic lesions. Recently, vitamin D₃ (VD₃) was found to be an effective and safe therapy for psoriasis. In the present study, we investigated the effects of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) and its analogue MC903 on IL-1α and IL-8 secretion by human keratinocytes in vitro. Cultured normal human keratinocytes (NHKs) produced considerable amounts of IL-1α but secreted less. In contrast, they produced less IL-8 and almost all molecules were secreted to the culture supernatants. Treatment of unstimulated NHKs with 1,25(OH)₂D₃ or MC903 showed little effects on IL-1α production and secretion though they slightly enhanced IL-8. When NHKs were stimulated with tumour necrosis factor-alpha (TNFα), both IL-1α and IL-8 secretions were enhanced and these enhancements were inhibited by 1,25(OH)₂D₃ or MC903. Stimulation of NHKs with phorbol 12-myristate 13-acetate(PMA) and lipopolysaccharide(LPS) resulted in an increase of IL-8 and decrease of IL-1α in the culture supernatants. Addition of 1,25(OH)₂D₃ or MC903 inhibited the increased secretion of IL-8 but restored decreased secretion of IL-1α from stimulated NHKs dose dependently. Hydrocortisone and cyclosporin A showed similar inhibitory effects on PMA/LPS-increased IL-8 secretion from NHKs but had little effect on restoring IL-1α. Cells of HSC-1, a human squamous cell carcinoma cell line, constitutively produced and secreted both IL-1α and IL-8. 1,25(OH)₂D₃ and MC903 inhibited the production of both cytokines. These results suggest that VD₃ is effective in terms of regulation of both IL-1α and IL-8 secretion by keratinocytes, which may contribute to its clinical efficacy for psoriasis.