A mediator role for metallothionein in tumor necrosis factor-induced lethal shock.
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).
Waelput
W
W
Department of Medical Protein Research, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B9000 Ghent, Belgium.
Broekaert
D
D
Vandekerckhove
J
J
Brouckaert
P
P
Tavernier
J
J
Libert
C
C
D000818:Animals; D019587:Dietary Supplements; D005260:Female; D008546:Melanoma, Experimental / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity*; D015032:Zinc / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein; D015032:Zinc