Zinc therapies exert beneficial effects in several cutaneous pathologies through their antiinflammatory properties, but target cells and mechanisms of action are still uncertain. We wondered whether markers of the keratinocyte activation state, such as the expression of immune surface antigens (ICAM-1 and HLA-DR) and the production of TNF-alpha, frequently detected in inflammatory reactions, may be reduced by zinc. For this purpose, we used normal human keratinocytes derived from plastic skin surgery and cultured in low-calcium medium (MCDB153). We studied the effects of ZnSO4 (12.5 to 50 microM) alone or in combination with IFN-gamma (5 U/ml), a mediator of inflammation produced by activated T-cells, or nickel (5-10 micrograms/ml), a sensitizing metal hapten. Using FACS analysis, we showed that the combination of zinc with nickel or the addition of ZnSO4 24 h before IFN-gamma or NiSO4 treatments reduced ICAM-1 expression on the keratinocyte surface (p < 0.01). However, zinc did not modify the IFN-gamma induced expression of HLA class II antigen on keratinocytes. Zn2+ could also reduce the TNF-alpha secretion of keratinocytes stimulated by IFN-gamma or Ni2+ during 48 h. Taken together, these data indicate that zinc can directly reduce some keratinocyte activation markers frequently observed in vivo; this action may be involved in the antiinflammatory effect of Zn(2+)-associated therapies in cutaneous inflammatory reactions.