DIFFERENTIATION OF HUMAN KERATINOCYTES IS ASSOCIATED WITH A PROGRESSIVE LOSS OF INTERFERON-GAMMA-INDUCED INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION

Intercellular adhesion molecule-1 (ICAM-1) expression is a necessary r equirement for leucocyte/keratinocyte interactions, and keratinocyte u pregulation of ICAM-1 is seen in several inflammatory dermatoses. Whil e keratinocytes have a very low constitutive expression of ICAM-1, the y can be induced to upregulate ICAM-1 in response to several inflammat ory cytokines, such as interferon-gamma (IFN gamma). There is some evi dence to suggest that the state of keratinocyte differentiation may in fluence the level of ICAM-1 expression induced by LFN gamma, The purpo se of this study was to investigate the hypothesis that keratinocytes, as they differentiate, may lose their ability to increase their expre ssion of ICAM-1 in response to IFN gamma. Keratinocytes from 13 donors were cultured under conditions which either permitted (Green's medium ) or inhibited (MCDB153) differentiation. The ICAM-1 expression in res ponse to IFN gamma was assessed by a sensitive, cell-based, ELISA, and related to the state of differentiation of the cells (as assessed by a quantitative assay for involucrin). While keratinocytes grown in MCD B153 remained responsive to IFN gamma throughout 4 days of culture, th e response of keratinocytes grown in Green's medium progressively decr eased, so that, by day 3, only a high concentration of IFN gamma (500 U/ml) led to a significant increase in ICAM-1 expression. After 4 days in culture, no upregulation of ICAM-1 was seen. The deterioration in the response of Green's-cultured keratinocytes to IFN gamma mirrored a n increase in their expression of involucrin in parallel cultures. Ove rall, our data demonstrate a progressive loss in the ability of kerati nocytes to upregulate ICAM-1 in response to IFN gamma, which is associ ated with differentiation of these cells. This would support the view that only basal proliferative keratinocytes are responsive to inflamma tory cytokines, and play a part in the initiation and amplification of inflammatory reactions in vivo.