Cetirizine and hydrocortisone differentially regulate ICAM-1 expression and chemokine release in cultured human keratinocytes.
BACKGROUND
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.


OBJECTIVE
Cetirizine and hydrocortisone were compared in their capacity to counteract human keratinocytes activation by IFNgamma. In particular, expression of immuno-modulatory membrane molecules and chemokine release have been examined.


METHODS
Keratinocyte cultures established from normal skin of healthy donors were activated by IFNgamma (100-500 U/mL) in the absence or presence of cetirizine (10(-3)-10(3) microM) or hydrocortisone (10(-3)-10(2) microM), 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).


RESULTS
Cetirizine at high concentrations (10(2)-10(3) microM) markedly inhibited IFNgamma-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 (10(2) microM) enhanced IFNgamma-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 IFNgamma-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 IFNgamma-stimulated keratinocytes. In contrast, hydrocortisone, but not cetirizine, reduced GM-CSF and IL-8 release.


CONCLUSIONS
The results indicate that cetirizine has the capacity to block the IFNgamma-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.
Albanesi
C
C
Laboratory of Immunology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.
Pastore
S
S
Fanales-Belasio
E
E
Girolomoni
G
G
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D019013:CD40 Antigens / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D017332:Cetirizine / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000187:drug effects*; D007371:Interferon-gamma / Q000008:administration & dosage / Q000494:pharmacology; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D006684:HLA-DR Antigens; D006634:Histamine H1 Antagonists; D016209:Interleukin-8; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006854:Hydrocortisone; D017332:Cetirizine