CETIRIZINE AND HYDROCORTISONE DIFFERENTIALLY REGULATE ICAM-1 EXPRESSION AND CHEMOKINE RELEASE IN CULTURED HUMAN KERATINOCYTES

Background Cetirizine is a H-1 histamine antagonist which possesses an ti-inflammatory properties through inhibition of leucocyte recruitment and activation, and reduction of ICAM-1 expression on mucosal epithel ial cells. No studies have addressed the potential anti-inflammatory a ctivities of cetirizine on skin keratinocytes. Objectives Cetirizine a nd hydrocortisone were compared in their capacity to counteract human keratinocytes activation by IFN gamma. In particular, expression of im muno-modulatory membrane molecules and chemokine release have been exa mined. Methods Keratinocyte cultures established from normal skin of h ealthy donors were activated by IFN gamma (100-500 U/mL) in the absenc e or presence of cetirizine (10(-3)-10(3) mu M) or hydrocortisone (10( -3)-10(2) mu M), and tested for expression of ICAM-1, HLA-DR, MHC clas s I and CD40 as well as for release of RANTES, IL-8, macrophage chemot actic protein-1 (MCP-1) and granulocyte macrophage-colony stimulating factor (GM-CSF). Results Cetirizine at high concentrations (10(2)-10(3 ) mu M) markedly inhibited IFN gamma-induced expression of membrane IC AM-1, HLA-DR and up-regulation of MHC class I, but had no effect on CD 40 expression. In contrast, hydrocortisone (10(2) mu M) enhanced IFN g amma-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 IFN gamma-treated keratinocytes. The i nhibiting and stimulating effects of cetirizine and hydrocortisone, re spectively, on ICAM-1 expression were confirmed at the mRNA level by N orthern blot analysis. Finally, cetirizine, but not hydrocortisone, in hibited the release of MCP-1 and RANTES from IFN gamma-stimulated kera tinocytes. In contrast, hydrocortisone, but not cetirizine, reduced GM -CSF and IL-8 release. Conclusions The results indicate that cetirizin e has the capacity to block the IFN gamma-induced activation of kerati nocytes, and thus can exert important regulatory effects on TH1 cell-m ediated immune responses in the skin. The high doses required for evid encing these activities suggest the potential benefits of a topical us e of cetirizine.