Inter&kin 1 (IL-l), present in high amounts in normal human skin without any sign of inflammation, suggests a complex mechanism by which its bioactivity is regulated. The specific receptor antagonist of IL-1 (IL-lra) was analyzed in human skin, sweat and cultured keratinocytes. Extracts of both skin and cultured keratinocytes blocked the binding of ['2sI]IL-1 to its receptor whereas sweat did not. The inhibitory activity was cell-associated, was not secrctcd by cultured keratinocytes, and IL-lra mRNA was identified in these cells. There was an inverse relationship between the level of IL-lra and that of IL-la andj3 since extracts of differentiating kerdtinocytes (DK) and higher IL-lra levels and expressed more mRNA for IL-lra than non-differentiated keratinocytcs (NDK), whereas NDK contained 4 times more IL-la and /? proteins than DK. This association of cell differentiation with a shift in agonist/antagonist ratio might be related to important autocrine or paracrine functions of IL-I in normal and inflamed human skin