Human keratinocytes are major producers of IL-18: predominant expression of the unprocessed form

The cytokine network in the skin is a tightly regulated system in which IL- 1 isoforms, as well as their receptors and antagonists have a central role. The recently discovered IL-1 isoform IL-18 (also known as interferon gamma -inducing factor (IGIF) or IL-1 gamma), promotes IFN-gamma expression by T cells in concert with IL-12, Because IFN-gamma plays an important role in m any inflammatory skin diseases by facilitating the development of Th1 cells , it is important to elucidate the role of mediators which regulate the pro duction of this cytokine. We demonstrate that human keratinocytes constitut ively express IL-18 at the mRNA as well as at the protein level. The protei n was mainly expressed intracellularly in the 24 kD unprocessed pro-form, b ut was also secreted. Histochemistry revealed a diffuse staining of IL-18 i n the epidermis of normal skin, which is in line with our in vitro data. Fu rthermore, we show that the level of IL-18 expressed in freshly isolated no rmal human epidermal cells, whether or not containing HLA-DR+ cells, signif icantly exceeded the expression levels of other cell types such as monocyte s and bronchial epithelial cells. Finally, our results show that stimulatio n of the keratinocyte cell line HaCaT with PMA LPS or IL-1 beta, does not s ignificantly affect intracellular or released (pro) IL-18 levels. These exp eriments show for the first time that human keratinocytes relative to monoc ytes, PBMC or leukocytes produce a considerably larger amount of pro-IL-18, which is also readily released. High constitutive levels of IL-18 may cont ribute to the skewing towards a Th1-like environment, which is apparent in many human inflammatory skin diseases.