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

Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Journal of Neuroscience Research (Impact Factor: 2.59). 08/2003; 73(4):481-96. DOI: 10.1002/jnr.10681
Source: PubMed


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.

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    • "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. "
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    • "IL-6 has been shown to increase in experimental models of both mild (Shohami et al., 1994; Holmin et al., 1997) and moderate/severe (Woodroofe et al., 1991; Taupin et al., 1993) TBI in rodents and has been detected at high levels for weeks following severe human brain injuries (Kossmann et al., 1995). In mice lacking IL-6, experimental cortical freeze injuries or cytotoxic brain injuries result in increased oxidative stress, decreased cell survival, and lengthened recovery times compared to WT mice, suggesting that in the absence of IL-6, the brain's intrinsic repair mechanisms are deficient (Penkowa et al., 2000, 2003). These data compliment a series of both human brain injury cases and in vitro studies, whereby IL-6 secretion leads to elevated production of NGF in astrocytes and suppresses the production of both TNF-α and IL-1β (Kushima et al., 1992; Kossmann et al., 1996; Ley et al., 2011). "
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    • "Activation of STAT3 through only gp130 by Interleukin-6 (IL-6) signaling is known to trigger reactive astrogliosis (Sofroniew, 2009). The role of IL-6 is ambivalent, depending on the animal model and the disease that occurs in the experimental paradigms (Campbell et al., 1993; Penkowa et al., 2003; Quintana et al., 2009). "
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