Metallothioneins are upregulated in symptomatic mice with astrocyte-targeted expression of tumor necrosis factor-alpha

Transgenic mice expressing TNF-alpha under the regulatory control of the GF AP gene promoter (GFAP-TNF alpha mice) exhibit a unique, late-onset chronic -progressive neurological disorder with meningoencephalomyelitis, neurodege neration, and demyelination with paralysis. Here we show that the metalloth ionein-I + II (MT-I + II) isoforms were dramatically upregulated in the bra in of symptomatic but not presymptomatic GFAP-TNF alpha mice despite TNF-al pha expression being present in both cases. lit situ hybridization analysis for MT-I RNA and radioimmunoassay results for MT-I + II protein revealed t hat the induction was observed in the cerebellum but not in other brain are as. Increased MT-I RNA levels occurred in the Purkinje and granular neurona l layers of the cerebellum but also in the molecular layer. Reactive astroc ytes, activated rod-like microglia, and macrophages, but not the infiltrati ng lymphocytes, were identified as the cellular sources of the MT-I + II pr oteins. in situ hybridization for MT-III RNA revealed a modest increase in the white matter of the cerebellum, which was confirmed by immunocytochemis try. MT-III immunoreactivity was present in cells which were mainly round o r amoeboid monocytes/macrophages. The pattern of expression of the differen t MT isoforms in the GFAP-TNF alpha mice differed substantially from that d escribed previously in GFAP-IL6 mice, demonstrating unique effects associat ed with the expression of each cytokine. The results suggest that the MT ex pression in the CNS reflects the inflammatory response and associated damag e rather than a direct role of the TNF-alpha in their regulation and suppor t a major role of these proteins during CNS injury. (C) 2000 Academic Press .