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 requirement for leucocyte/keratinocyte interactions, and keratinocyte upregulation of ICAM-1 is seen in several inflammatory dermatoses. While keratinocytes have a very low constitutive expression of ICAM-1, they can be induced to upregulate ICAM-1 in response to several inflammatory cytokines, such as interferon-gamma (IFN gamma). There is some evidence to suggest that the state of keratinocyte differentiation may influence the level of ICAM-1 expression induced by LFN gamma, The purpose of this study was to investigate the hypothesis that keratinocytes, as they differentiate, may lose their ability to increase their expression 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 response 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 MCDB153 remained responsive to IFN gamma throughout 4 days of culture, the response of keratinocytes grown in Green's medium progressively decreased, 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 an increase in their expression of involucrin in parallel cultures. Overall, our data demonstrate a progressive loss in the ability of keratinocytes to upregulate ICAM-1 in response to IFN gamma, which is associated with differentiation of these cells. This would support the view that only basal proliferative keratinocytes are responsive to inflammatory cytokines, and play a part in the initiation and amplification of inflammatory reactions in vivo.