Altered central nervous system cytokine-growth factor expression profiles and angiogenesis in metallothionein-I plus II deficient mice

To study the importance of metallothionein-I and II (MT-I+II) for brain inf lammation and regeneration, the authors examined normal and MT-I+II knock-o ut (MT-KO) mice subjected to a cortical freeze injury. Normal mice showed p rofound neurodegeneration, inflammation, and gliosis around the injury, whi ch was repaired by 20 days postlesion (dpl). However. in MT-KO mice the les ion-associated inflammation was still present as late as 90 dpl. Scanning e lectron microscopy demonstrated that the number of capillaries was lower, a nd ultrastructural preservation of the lesioned parenchyma was poorer in MT -KO mice, suggesting an altered angiogenesis. To nain insight into the mech anisms involved, a number of cytokines and growth factors were evaluated. T he number of cells expressing the proinflammatory cytokines IL-I beta, IL-6 , and TNF-alpha was higher in MT-KO mice than in normal mice, which was con firmed by RNase protection analysis, whereas the number of cells expressing the growth factors bFGF, TGF beta 1, VEGF, and NT-3 was lower. Increased e xpression of proinflammatory cytokines could be involved in the sustained r ecruitment of CD-14+ and CD-34+ inflammatory cells and their altered functi ons observed in MT-KO mice. Decreases in trophic factors bFGF, TGF beta 1, and VEGF could mediate the decreased angiogenesis and regeneration observed in MT-KO mice after the freeze lesion. A role for MT-I+II in angiogenesis was also observed in transgenic mice expressing IL-6 under the control of t he promoter of glial fibrillary acidic protein gene (GFAP-IL6 mice) because MT-I+II deficiency dramatically decreased the IL-6-induced angiogenesis of the GFAP-IL6 mice. In situ hybridization analysis indicated that the MT-II I expression was not altered by MT-I+II deficiency. These results suggest t hat the MT-I+II isoforms have major regulatory functions in the brain infla mmatory response to injury, especially in the angiogenesis process.