Cetirizine and hydrocortisone differentially regulate ICAM‐1 expression and chemokine release in cultured human keratinocytes

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Abstract
Cetirizine is a H1 histamine antagonist which possesses anti-inflammatory properties through inhibition of leucocyte recruitment and activation, and reduction of ICAM-1 expression on mucosal epithelial cells. No studies have addressed the potential anti-inflammatory activities of cetirizine on skin keratinocytes. Cetirizine and hydrocortisone were compared in their capacity to counteract human keratinocytes activation by IFNγ. In particular, expression of immuno-modulatory membrane molecules and chemokine release have been examined. Keratinocyte cultures established from normal skin of healthy donors were activated by IFNγ (100–500 U/mL) in the absence or presence of cetirizine (10−3–103 μM) or hydrocortisone (10−3–102 μM), and tested for expression of ICAM-1, HLA-DR, MHC class I and CD40 as well as for release of RANTES, IL-8, macrophage chemotactic protein-1 (MCP-1) and granulocyte macrophage-colony stimulating factor (GM-CSF). Cetirizine at high concentrations (102–103 μM) markedly inhibited IFNγ-induced expression of membrane ICAM-1, HLA-DR and up-regulation of MHC class I, but had no effect on CD40 expression. In contrast, hydrocortisone (102 μM) enhanced IFNγ-induced membrane ICAM-1, reduced expression of HLA-DR and did not alter expression of MHC class I and CD40. Consistently, high doses of cetirizine decreased, whereas hydrocortisone increased, soluble ICAM-1 levels in the supernatants of IFNγ-treated keratinocytes. The inhibiting and stimulating effects of cetirizine and hydrocortisone, respectively, on ICAM-1 expression were confirmed at the mRNA level by Northern blot analysis. Finally, cetirizine, but not hydrocortisone, inhibited the release of MCP-1 and RANTES from IFNγ-stimulated keratinocytes. In contrast, hydrocortisone, but not cetirizine, reduced GM-CSF and IL-8 release. The results indicate that cetirizine has the capacity to block the IFNγ-induced activation of keratinocytes, and thus can exert important regulatory effects on TH1 cell-mediated immune responses in the skin. The high doses required for evidencing these activities suggest the potential benefits of a topical use of cetirizine.