Interferon-γ (IFN-γ) 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-γ 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-γ receptor gene (IFN-γR-/-). Liver MT-I mRNA and MT-(I+II) protein levels during stress of IFN-γR-/- 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-γR-/- mice than in the other strains. MT-I+II response to LPS was also higher in IFN-γR-/- 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-γ 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-γ 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. © Harcourt Brace & co. Ltd 1997.