Arsenic induces overexpression of growth factors in human keratinocytes.
Although epidemiological studies have shown that inorganic arsenicals are human skin carcinogens and induce hyperproliferation and hyperkeratosis, there is currently no known mechanism for their action or an established animal model for its study. We observed increased mRNA transcripts and secretion of keratinocyte growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-alpha (TGF alpha) and the proinflammatory cytokine tumor necrosis factor-alpha in primary human epidermal keratinocytes cultured in the presence of low micromolar concentrations of sodium arsenite. Treatment with sodium arsenite resulted in a significant increase in cell proliferation, as indicated by increases in cell numbers, c-myc gene expression, and incorporation of [3H]thymidine into cellular DNA. Studies of transcriptional regulation indicate that the rate of GM-CSF mRNA transcription is increased, while the elevated TGF alpha is likely the results of message stabilization. While a number of cytokine regulatory networks exist in the skin, studies utilizing neutralizing antibodies against the growth factors of interest indicate that inhibition of the arsenic-induced increase in TGF alpha results in a corresponding decrease in the gene expression and secretion of GM-CSF. The present studies demonstrate that growth-promoting cytokines and growth factors are induced in keratinocytes following treatment with arsenic and could play a significant role in arsenic-induced skin cancer.
Germolec
D R
DR
Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. GERMOLEC@NIEHS.NIH.GOV
Yoshida
T
T
Gaido
K
K
Wilmer
J L
JL
Simeonova
P P
PP
Kayama
F
F
Burleson
F
F
Dong
W
W
Lange
R W
RW
Luster
M I
MI
D018053:Arsenites / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D017670:Sodium Compounds / Q000633:toxicity*; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018053:Arsenites; D017670:Sodium Compounds; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; C017947:sodium arsenite; D016178:Granulocyte-Macrophage Colony-Stimulating Factor