Sodium arsenate induces overproduction of interleukin-1alpha in murine keratinocytes: role of mitochondria.
It has recently been demonstrated that arsenic induces overexpression of keratinocyte-derived growth factors, which are likely to have a significant role in arsenic-induced skin hyperkeratoses and cancer. The mechanism(s) involved in this induction are, however, still elusive. The purpose of this study was to investigate the early intracellular events that follow in vitro treatment with sodium arsenate in a murine keratinocyte cell line (HEL30), which leads to cytokine overproduction. First, we observed that sodium arsenate induced a concentration-dependent production of interleukin-1alpha and a significant increase in cell proliferation, that could be suppressed by the addition of a neutralizing antibody against murine interleukin-1alpha, confirming the ability of arsenic to induce keratinocyte growth-promoting cytokines. Electron microscopic analysis revealed that arsenate induced a dramatic alteration in keratinocyte mitochondria. This effect could be prevented by rotenone pretreatment, which suggests the possible involvement of mitochondria-derived reactive oxygen species. Arsenic induced a concentration- and time-dependent increase in cellular oxidative activity, which was followed by activation of redox-sensitive transcription factors such as nuclear factor-kappaB and activator protein-1, that are essential for interleukin-1alpha synthesis. Prior treatment with rotenone or prolonged treatment with ethidium bromide, an inhibitor of mitochondrial DNA and RNA synthesis, to deplete cells of functional mitochondria, completely prevented sodium arsenate-induced interleukin-1alpha production, this indicates the pivotal role of these organelles in sodium arsenate-induced keratinocyte growth factors.
Corsini
E
E
Laboratory of Toxicology, Institute of Pharmological Sciences, University of Milan, Italy. emanuela.corsini@unimi.it
Asti
L
L
Viviani
B
B
Marinovich
M
M
Galli
C L
CL
D000818:Animals; D001149:Arsenates / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D007375:Interleukin-1 / Q000096:biosynthesis*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014475:Uncoupling Agents / Q000494:pharmacology
D001149:Arsenates; D007375:Interleukin-1; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; C009277:sodium arsenate