Human keratinocytes constitutively express interleukin-18 and secrete biologically active interleukin-18 after treatment with pro-inflammatory mediators and dinitrochlorobenzene

Interleukin-18 is a potent inducer of interferon-gamma by activated T cells , macrophages, and monocytes and is synthesized as an inactive precursor. P ro-interleukin-18 must be cleaved by interleukin-1-beta-converting enzyme f or secretion of the biologically active form. We report that among selected non-bone marrow derived skin cells, interleukin-18 mRNA is constitutively expressed by human keratinocytes and not by dermal microvascular endothelia l cells, dermal fibroblasts, or melanocytes. Interleukin-18 mRNA and intrac ellular protein levels are neither changed in human keratinocytes nor induc ed in human dermal microvascular endothelial cells, dermal fibroblasts, or melanocytes by exposure to pro-inflammatory stimuli. Exposure of human kera tinocytes to phorbol 12-myrisate 13-acetate, lipopolysaccharides or the con tact sensitizer DNCB results in the secretion of immunoprecipitable interle ukin-18 protein. Human keratinocyte-secreted interleukin-18 is biologically active, in that conditioned media from phorbol 12-myrisate 13-acetate, lip opolysaccharide and DNCB-treated human keratinocytes induce interferon-gamm a expression by peripheral blood mononuclear cells, This bioactivity is neu tralized by anti-interleukin-18, but not anti-interleukin-12 antibodies. By immunohistochemistry, interleukin-18 protein is detected in basal keratino cytes of normal human skin, but its expression is markedly upregulated in s uprabasal keratinocytes in psoriasis, These findings indicate that human ke ratinocytes are a source of biologically functional interleukin-18 and thus are capable of playing an initiating part in the local interferon-gamma-de pendent inflammatory processes through expression, activation, and secretio n of interleukin-18.