ROLE OF KERATINOCYTE-DERIVED CYTOKINES IN CHEMICAL TOXICITY

Following appropriate stimulation, such as with tumor promoters, ultra violet light or various chemical agents, keratinocytes synthesize and secrete cytokines which can mediate or participate in dermatotoxic res ponses such as inflammation, hyperkeratosis, hypersensitivity and skin cancer. We have determined the qualitative and quantitative cytokine response in primary human keratinocyte cultures following exposure to several non-sensitizing contact irritants, sensitizers and ulcerative agents as well as a skin carcinogen. The chemicals were also administe red to mice to assess whether the dermatotoxic response correlated wit h the in vitro production of keratinocyte-derived cytokines. Due to th e complex cellular interactions that occur in the skin, it was not pos sible to identify specific cytokine profiles for most of the classes o f dermatotoxic agents studied. However, the non-sensitizing contact ir ritants produced relative increases in the synthesis and secretion of the proinflammatory cytokines, interleukin-1 and tumor necrosis factor -alpha, as well as the neutrophil chemotactic cytokine, interleukin-8 compared to the other chemical agents, While ulcerative compounds as w ell as irritants elicited neutrophils to the site of chemical applicat ion when applied to the mouse skin, time-dependent and chemical-specif ic patterns of inflammation were detected. Treatment of human keratino cyte cultures with arsenic, a human skin carcinogen, resulted in a uni que cytokine profile characterized by induction of growth factors, inc luding transforming growth factor-alpha and granulocyte-macrophage col ony stimulating factor. Treatment of v-Ha-ras transgenic mice, an anim al model for skin cancer, with arsenic caused an increase in the numbe r of papillomas as well as overexpression of these growth factors sugg esting that they participate in arsenic-induced skin papilloma develop ment. These studies indicate a diverse role exists for keratinocyte-de rived cytokines in dermatotoxic actions.