The Journal of Experimental Medicine
Keystone Symposia
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Published 3 December 2001. doi:10.1084/jem.194.11.1617
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© Rockefeller University Press, 0022-1007/2001/12/1617/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1617-1624

Brief Definitive Report

 A Mediator Role For Metallothionein in Tumor Necrosis Factor–induced Lethal Shock

Wim Waelput1, Daniël Broekaert1, Joël Vandekerckhove1, Peter Brouckaert2, Jan Tavernier1 and Claude Libert2

1 Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B9000 Ghent, Belgium
2 Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B9000 Ghent, Belgium

Address correspondence to J. Tavernier, Klugskensstraat 31-33, B9000 Ghent, Belgium. Phone: 32-9-3313302; Fax: 32-9-3313599; E-mail: Jan.Tavernier{at}rug.ac.be

Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is centrally involved in several inflammatory disorders. Administration of TNF leads to a potentially lethal systemic inflammatory response syndrome (SIRS). We observed that (a) mice lacking functional genes for metallothionein 1 and 2 (MT-null) were protected compared with wild-type controls (P = 0.0078), and (b) mice overexpressing MT-1 (MT-TG) were more sensitized for the lethal effect of TNF than control mice (P = 0.0003), indicating a mediating role for MT in TNF induced SIRS. As MT is involved in the body zinc homeostasis, we tested whether zinc-deprivation or -supplementation alters the response to TNF. Although zinc-depletion strongly sensitized (P = 0.036), and pretreatment with zinc sulfate (ZnSO4) conferred protection against the deleterious effects of TNF (P < 0.0002), it was also found that the protection provided by zinc is independent of MT. Our observation that hsp70 is strongly induced in jejunum after ZnSO4 treatment, suggests a contribution of hsp70 in the protection against TNF. In addition, ZnSO4 cotreatment allowed complete regression of inoculated tumors with TNF and interferon {gamma}, leading to a significantly better survival (P = 0.0045).

Key Words: systemic inflammatory response syndrome • zinc • acute-phase reaction • interferon • leptin


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