INDUCTION OF INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION ON NORMAL HUMAN KERATINOCYTES BY RETINOIC ACID - COMPARISON OF CULTURED KERATINOCYTES AND SKIN EXPLANTS

As retinoic acid (RA, all trans) induces irritant reactions when applied topically to skin, we wondered whether it may be involved in the activation state of keratinocytes through ICAM-1 induction. Human skin explants and cultured keratinocytes were treated by RA and /or interferon-gamma (IFN gamma) at different concentrations during 24, 48 and 72 h. ICAM-1 expression was examined and quantified by immunohistochemistry, in situ, on cutaneous frozen sections and in cultured keratinocytes by flow cytometry analysis. Expression of mRNA was checked by Northern blot hybridizations using an oligonucleotide probe. Our results indicate: (1) the absence of spontaneous ICAM-1 expression by normal human keratinocytes both in skin explants and in cultures; (2) an ICAM-1-induced expression after 48 h of treatment by RA concentrations >10(-6) M; this induction is dose- and time-dependent; in skin explants, ICAM-1 is occasionally observed on foci of epidermal cells; this protein induction is correlated with transcript expression in cultured keratinocytes; and (3) a synergistic effect of RA and IFN gamma (5 IU/ml) on the percentage of ICAM-1-positive cells and the level of expression of the protein. These findings indicate that RA, in a therapeutical range of concentrations, can induce or stimulate ICAM-1 expression in normal human keratinocytes. This may in part explain the erythematous reaction observed in vivo after topical applications of RA which may be considered as a mediator of keratinocyte activation.