Metallothionein‐I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte‐targeted interleukin‐6 expression

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Abstract
Transgenic expression of IL‐6 in the CNS under the control of the GFAP gene promoter, glial fibrillary acidic protein‐interleukin‐6 (GFAP‐IL‐6) mice, raises an inflammatory response and causes significant brain damage. However, the results obtained in the GFAP‐IL‐6 mice after a traumatic brain injury, such as a cryolesion, demonstrate a neuroprotective role of IL‐6. Thus, the GFAP‐IL‐6 mice showed faster tissue repair and decreased oxidative stress and apoptosis compared with control litter‐mate mice. The neuroprotective factors metallothionein‐I+II (MT‐I+II) were upregulated by the cryolesion to a higher extent in the GFAP‐IL‐6 mice, suggesting that they could be related to the neuroprotection afforded by the transgenic expression of IL‐6. To examine this possibility, we have crossed GFAP‐IL‐6 mice with transgenic mice overexpressing MT‐I (TgMT), producing double transgenic GFAP‐IL‐6 TgMT mice. The results obtained after cryolesion in GFAP‐IL‐6 TgMT mice, as well as in TgMT mice, consistently supported the idea that the increased MT‐I+II levels observed in GFAP‐IL‐6 mice are a fundamental and important mechanism for coping with brain damage. Accordingly, MT‐I overexpression regulated the inflammatory response, decreased oxidative stress and apoptosis significantly, and increased brain tissue repair in comparison with either GFAP‐IL‐6 or control litter‐mate mice. Overall, the results demonstrate that brain MT‐I+II proteins are fundamental neuroprotective factors. GLIA 42:287–306, 2003.