Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide.
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.
Penkowa
Milena
M
Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Camats
Jordi
J
Hadberg
Hanne
H
Quintana
Albert
A
Rojas
Santiago
S
Giralt
Mercedes
M
Molinero
Amalia
A
Campbell
Iain L
IL
Hidalgo
Juan
J
D015120:6-Aminonicotinamide; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D002452:Cell Count / Q000379:methods; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018390:Gene Targeting; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000502:physiology; D013194:Staining and Labeling / Q000379:methods; D013234:Stem Cells / Q000378:metabolism; D013723:Teratogens; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D006133:Growth Substances; D015850:Interleukin-6; D013723:Teratogens; D015120:6-Aminonicotinamide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D008668:Metallothionein