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

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-alpha as well as growth factors basic fibroblast growth factor (bFGF), transforming growth factor-beta, 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.

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

“…Further clinical evaluation was stopped because the neurotoxicity limited dose escalation. The cause of this side effect is not known, though it is theorized to be due to the death of glial cells by 6-AN (Kim and Wenger, 1973;Penkowa et al, 2003). Importantly, in contrast to what was observed with 6-AN, in our xenograft experiments thionicotinamide did not cause neurotoxicity in mice, suggesting that other inhibitors of NADK and or G6PD may not induce this deleterious side effect.…”

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

“…37 Concordantly, in experiments using the same injury model mice deficient for IL-6 exhibited increased oxidative stress, decreased cell survival, and delayed wound healing, 38 indicating that IL-6 is required for repair.…”

Traumatic Brain Injury and Inflammation: Emerging Role of Innate and Adaptive Immunity

“…IL-6 was found at elevated levels in experimental TBI (Shohami et al, 1994). Mice deficient for IL-6 had increased numbers of apoptotic neurons, increased oxidative stress and delayed healing of the tissue (Penkowa et al, 2000), whereas the same group demonstrated that IL-6 transgenic mice exhibited increased reduction of oxidative stress and apoptotic cell death after a cryogenic brain injury (Penkowa et al, 2003). Tumor necrosis factor-a (TNFa) is another cytokine with a well-documented role in TBI.…”