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.