Astrocyte-targeted expression of interleukin-3 and interferon-alpha causesregion-specific changes in metallothionein expression in the brain

Transgenic mice expressing IL-3 and IFN-alpha under the regulatory control of the GFAP gene promoter (GFAP-IL3 and GFAP-IFN alpha mice) exhibit a cyto kine-specific, late-onset chronic-progressive neurological disorder which r esemble many of the features of human diseases such as multiple sclerosis, Aicardi-Goutieres syndrome, and some viral encephalopathies including HIV l eukoencephalopathy. In this report we show that the metallothionein-I+II (M T-I+II) isoforms were upregulated in the brain of both GFAP-ILS and GFAP-IF N alpha mice in accordance with the site and amount of expression of the cy tokines, In the GFAP-IL3 mice, in situ hybridization analysis for MT-I RNA and radioimmunoassay results for MT-I+II protein revealed that a significan t upregulation was observed in the cerebellum and medulla plus pens at the two ages studied, 1-3 and 6-10 months. Increased MT-I RNA levels occurred i n the Purkinje and granular layers of the cerebellum, as well as in its whi te matter tracts. In contrast to the cerebellum and brain stem, MT-I+II wer e downregulated by IL-3 in the hippocampus and the remaining brain in the o lder mice. In situ hybridization for MT-III RNA revealed a modest increase in the cerebellum, which was confirmed by immunohistochemistry, MT-III immu noreactivity was present in cells that were mainly round or amoeboid monocy tes/macrophages and in astrocytes, MT-I+II induction was more generalized i n the GFAP-IFN alpha (GIFN12 and GIFN39 lines) mice, with significant incre ases in the cerebellum, thalamus, hippocampus, and cortex. In the high expr essor line GIFN39, MT-III RNA levels were significantly increased in the ce rebellum (Purkinje, granular, and molecular layers), thalamus, and hippocam pus (CA2/CA3 and especially lacunosum moleculare layers). Reactive astrocyt es, activated rodlike microglia, and macrophages, but not the perivenular i nfiltrating cells, were identified as the cellular sources of the MT-I+II a nd MT-III proteins, The pattern of expression of the different MT isoforms in these transgenic mice differed substantially, demonstrating unique effec ts associated with the expression of each cytokine, The results indicate th at the MT expression in the CNS is significantly affected by the cytokine-i nduced inflammatory response and support a major role of these proteins dur ing CNS injury, (C) 2001 Academic Press.