Nickel-induced keratinocyte proliferation and up-modulation of the keratinocyte growth factor receptor expression.
Keratinocytes play a key role in the pathogenesis of allergic contact dermatitis (ADC) induced by the sensitizing agent nickel. We analyzed here the effects of treatment with nickel and of the pretreatment with zinc on HaCaT cells and primary human keratinocytes. Cell counting, 5-bromo-2'-deoxyuridine incorporation assay and adenosine triphosphate (ATP) bioluminescence detection showed that treatment with NiSO4 induced DNA synthesis and cell proliferation and that pretreatment with ZnSO4 was able to abrogate this proliferative effect. This nickel-induced cell growth appeared enhanced when primary human keratinocytes were co-cultured with fibroblasts. Western blot analysis demonstrated that nickel ions induced up-modulation of the expression of the keratinocyte growth factor receptors (KGFR) without affecting the keratinocyte differentiation, whereas the protein levels of the epidermal growth factor receptor (EGFR) and of its ligand transforming growth factor-alpha (TGF-alpha) appeared unmodified by the treatment. Double immunofluorescence showed that the effect of nickel on DNA synthesis was mainly exerted on KGFR expressing cells, suggesting that KGFR up-modulation could be required for the nickel-induced cell proliferation. These results indicate that KGFR and its ligands may play a role in the mechanism of action of nickel ions and in the protective effect of zinc pretreatment.
Marchese
Cinzia
C
Dipartimento di Medicina Sperimentale e Patologia, Università di Roma 'La Sapienza'; Istituto Dermatologico San Gallicano, Roma, Italy.
Visco
Vincenzo
V
Aimati
Laura
L
Cardinali
Giorgia
G
Kovacs
Daniela
D
Buttari
Brigitta
B
Bellocci
Marinella
M
Torrisi
Maria Rosaria
MR
Picardo
Mauro
M
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D017449:Dermatitis, Allergic Contact / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008854:Microscopy, Electron; D009532:Nickel / Q000633:toxicity*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000633:toxicity
C496453:FGF7 protein, human; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D009532:Nickel; D004247:DNA; D066246:ErbB Receptors; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; D015032:Zinc