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International Immunology, Vol. 7, No. 3, pp. 343-352,March 1995
© 1995 Japanese Society for Immunology
Nickel and skin irritants up-regulate tumor necrosis factor-
mRNA in keratinocytes by different but potentially synergistic mechanisms
Department of Dermatology, Hôpital Cantonal Universitaire 24 Rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland
1 Ludwig Institute for Cancer Research 155 Chemin des Boveresses, CH-1066 Epalinges, Switzerland
Correspondence to: Correspondence to: C. Hauser
A critical role of tumor necrosis factor (TNF)-
in irritant contact dermatitis and in the challenge phase of allergic contact dermatitis has recently been demonstrated in vivo. As in situ hybridization studies have indicated that keratinocytes were the cellular source of TNF- in these reactions, we studied the mechanisms of TNF- mRNA induction in keratinocytes by agents that induce contact dermatitis. Murine Ia–;/CD3– epidermal cells were stimulated with phorbol myristate acetate (PMA), dimethylsulfoxide (DMSO), sodium dodecyl sulfate (SDS) and NiSO4, all of which up-regulated epidermal cell TNF- mRNA production. In contrast, trinitrobenzenesulfonic acid and trinitrochlorobenzene did not significantly up-regulate TNF- mRNA. These results were confirmed with murine keratinocyte cell lines. In keratinocytes transfected with a chloramphenicol acetyltransferase construct containing the –1059 to +138 base pair TNF- promoter, increased promoter activity was observed upon stimulation with PMA and DMSO. In addition, PMA stimulation did not affect the stability of TNF- mRNA. The PMA- but also the DMSO- and SDSinduced up-regulation of TNF- mRNA was abolished by an inhibitor of protein kinase C (PKC). In contrast, NISO4 up-regulated TNF- mRNA by a PKC-independent mechanism, did not increase TNF- promoter activity, but markedly increased the stability of the TNF- mRNA. Co-stimulation with PMA and NISO4 induced a marked increase in TNF-a mRNA over that obtained with each agent alone. Thus, whereas PKC-dependent irritants act by up-regulating TNF- promoter activity, nickel acts via post-transcrlptional regulation. Our results, also establish that some irritants and irritant sensitizers directly induce TNF- in keratinocytes without intermediate Langerhans cell derived signals.
Keywords: contact dermatitis, transcription, tumor necrosis factor-
Received 21 September 1994, accepted 12 November 1994.
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