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

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.

Activation of Inflammatory Response by a Combination of Growth Factors in Cuprizone-Induced Demyelinated Brain Leads to Myelin Repair

“…In contrast, transgenic mice over expressing MT I/II displayed less severe inflammatory responses of macrophages and lymphocytes including decreased levels of pro-inflammatory cytokines and ROS [43,47,48]. In agreement with the findings described in MS that increased levels of MT are involved in disease remission and clinical recovery [49,50], we found a significant increase in MT I/II mRNA and protein levels in cuprizone-induced demyelinated brain and MTII mRNA in GFs-induced remyelination. The expression of MT was primarily associated with the astrocytes, while a low level was also detected in activated microglia [51][52][53].…”

Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

“…Cell counts were performed from three sections per mouse in all mice. Positively vs. negatively stained cells were previously demonstrated in detail Penkowa et al, 2003).…”

The Role of Neuroinflammation in Traumatic Brain Injury

“…In addition to neurotrophin induction, the neuropoietic cytokines like IL-6 have been shown to possess additional mechanisms of neuroprotection in TBI models, by mediating the generation of antioxidants, such as metallothioneins [113,181]. Furthermore, the intracranial activation of the complement cascade has been shown to mediate neuroprotective effects aside from the previously known neuroinflammatory and deleterious functions [135,140,166].…”