Astrocyte‐targeted expression of interleukin‐6 protects the central nervous system during neuroglial degeneration induced by 6‐aminonicotinamide

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Abstract
6‐Aminonicotinamide (6‐AN) is a niacin antagonist, which leads to degeneration of gray matter astrocytes mainly in the brainstem. We have examined the role of interleukin‐6 (IL‐6) in this degenerative process by using transgenic mice with astrocyte‐targeted IL‐6 expression (GFAP‐IL6 mice). This study demonstrates that transgenic IL‐6 expression significantly increases the 6‐AN‐induced inflammatory response of reactive astrocytes, microglia/macrophages, and lymphocytes in the brainstem. Also, IL‐6 induced significant increases in proinflammatory cytokines IL‐1, IL‐12, and tumor necrosis factor‐α as well as growth factors basic fibroblast growth factor (bFGF), transforming growth factor‐β, neurotrophin‐3, angiopoietin, vascular endothelial growth factor, and the receptor for bFGF. In accordance, angiogenesis was increased in GFAP‐IL6 mice relative to controls after 6‐AN. Moreover, oxidative stress and apoptotic cell death were significantly reduced by transgenic IL‐6 expression. IL‐6 is also a major inducer in the CNS of metallothionein I and II (MT‐I+II), which were significantly increased in the GFAP‐IL6 mice. MT‐I+II are antioxidants and neuroregenerative factors in the CNS, so increased MT‐I+II levels in GFAP‐IL6 mice could contribute to the reduction of oxidative stress and cell death in these mice.