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Prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) is pro\u2010inflammatory at the onset of inflammation and anti\u2010inflammatory at its resolution. We hypothesized that induction of PGE<jats:sub>2<\/jats:sub> synthesis by calcitriol in epidermal keratinocytes may contribute both to its pro\u2010inflammatory and anti\u2010inflammatory effects on the skin. Treatment of human immortalized HaCaT keratinocytes with calcitriol (3\u2013100\u2009nM, 2\u201324\u2009h) increased PGE<jats:sub>2<\/jats:sub> production due to increased mRNA and protein expression of COX\u20102, but not to increase of COX\u20101 or release of arachidonic acid. The effect of calcitriol on COX\u20102 mRNA was observed also in primary human keratinocytes. The increase in COX\u20102 mRNA is associated with COX\u20102 transcript stabilization. Calcitriol exerts this effect by a rapid (2\u2009h) and protein synthesis independent mode of action that is dependent on PKC and Src kinase activities. Treatment with a COX\u20102 inhibitor partially prevented the attenuation of the keratinocyte inflammatory response by calcitriol. We conclude that upregulation of COX\u20102 expression with the consequent increase in PGE<jats:sub>2<\/jats:sub> synthesis may be one of the mechanisms explaining the Janus face of calcitriol as both a promoter and attenuator of cutaneous inflammation. J. Cell. 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