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.
- SourceAvailable from: P. M. Abdul Muneer[Show abstract] [Hide abstract]
ABSTRACT: Traumatic brain injury (TBI) is a major cause of death in the young age group and leads to persisting neurological impairment in many of its victims. It may result in permanent functional deficits because of both primary and secondary damages. This review addresses the role of oxidative stress in TBI-mediated secondary damages by affecting the function of the vascular unit, changes in blood-brain barrier (BBB) permeability, posttraumatic edema formation, and modulation of various pathophysiological factors such as inflammatory factors and enzymes associated with trauma. Oxidative stress plays a major role in many pathophysiologic changes that occur after TBI. In fact, oxidative stress occurs when there is an impairment or inability to balance antioxidant production with reactive oxygen species (ROS) and reactive nitrogen species (RNS) levels. ROS directly downregulate proteins of tight junctions and indirectly activate matrix metalloproteinases (MMPs) that contribute to open the BBB. Loosening of the vasculature and perivascular unit by oxidative stress-induced activation of MMPs and fluid channel aquaporins promotes vascular or cellular fluid edema, enhances leakiness of the BBB, and leads to progression of neuroinflammation. Likewise, oxidative stress activates directly the inflammatory cytokines and growth factors such as IL-1β, tumor necrosis factor-α (TNF-α), and transforming growth factor-beta (TGF-β) or indirectly by activating MMPs. In another pathway, oxidative stress-induced degradation of endothelial vascular endothelial growth factor receptor-2 (VEGFR-2) by MMPs leads to a subsequent elevation of cellular/serum VEGF level. The decrease in VEGFR-2 with a subsequent increase in VEGF-A level leads to apoptosis and neuroinflammation via the activation of caspase-1/3 and IL-1β release.Molecular neurobiology. 05/2014;
- Annals of Physical and Rehabilitation Medicine. 01/2011; 54.