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IFN-R -/- mice show an enhanced liver and brain metallothionein I+II response to endotoxin but not to immobilization stress

Departamento de Biología Celular y Fisiologfa, Unidad de Fisiologfa Animal, Facultad de Ciencias

J. Carrasco

Departamento de Biología Celular y Fisiologfa, Unidad de Fisiologfa Animal, Facultad de Ciencias

M.L. Arbonés

Departamento de Bioqufmica y Biologia Molecular y Instituto de Biologia Fundamental, Universidad Autónoma de Barcelona, Bellaterra, Barcelona, Spain

J. Hidalgo

Departamento de Biología Celular y Fisiologfa, Unidad de Fisiologfa Animal, Facultad de Ciencias, Hidalgo{at}cc.uab.es

Interferon- (IFN-) is known for its important antiviral activity and other immunomodulatory actions. In in vitro studies, this cytokine has also been involved in the control of metallothionein (MT) synthesis. MT is a low molecular weight protein comprised of several isoforms called MT-I to MT-IV; of these, MT-1+11 are widely expressed, whereas MT-III and MT-IV are rather tissue specific. In the present report, we have studied in vivo the role of IFN- for a normal liver and brain MT-I+II response to immobilization stress and to an inflammatory process caused by bacterial lipopolysaccharide (LPS, endotoxin), using mice carrying a null mutation in the IFN- receptor gene (IFN-R^-/-). Liver MT-I mRNA and MT-(I+II) protein levels during stress of IFN-R^-/- mice were similar to those of the two parental mouse strains used to generate them, namely C57BU6 and 129/Sv mice, and that of the F₁ C57BU6 x 129/Sv offspring mice. In contrast, liver MT response to LPS was significantly higher in the IFN-R^-/- mice than in the other strains. MT-I+II response to LPS was also higher in IFN-R^-/- mice in medulla plus pons and tended to in hypothalamus, hippocampus, and cerebellum, but not in the remaining brain. These results suggest that a role of IFN- on liver and brain MT-I+II response to stress is unlikely, but that this cytokine exerts an inhibitory effect on the signaling pathways activated by LPS involved in MT-I+II regulation. In situ hybridization analysis for MT-I and MT-III mRNAs of control mice revealed significant effects of the functional IFN- deficiency on MT-I but not MT-III mRNA levels in the dentate gyrus and the habenula, while no effects were observed in the remaining brain areas studied.

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				M. Penkowa, J. Carrasco, M. Giralt, T. Moos, and J. Hidalgo CNS Wound Healing Is Severely Depressed in Metallothionein I- and II-Deficient Mice J. Neurosci., April 1, 1999; 19(7): 2535 - 2545. [Abstract] [Full Text] [PDF]