title: IL-6 deficiency leads to reduced metallothionein-I+II expression and increased oxidative stress in the brain stem after 6-aminonicotinamide treatment.
abstract: We examined the effects of interleukin-6 (IL-6) deficiency on brain inflammation and the accompanying bone marrow (BM) leukopoiesis and spleen immune reaction after systemic administration of a niacin antagonist, 6-aminonicotinamide (6-AN), which causes both astroglial degeneration/cell death in brain stem gray matter areas and BM toxicity. In both normal and genetically IL-6-deficient mice (IL-6 knockout (IL-6KO) mice), the extent of astroglial degeneration/cell death in the brain stem was similar as determined from disappearance of GFAP immunoreactivity. In 6-AN-injected normal mice reactive astrocytosis encircled gray matter areas containing astroglial degeneration/cell death, which were infiltrated by several macrophages and some T-lymphocytes. Reactive astrocytes and a few macrophages increased significantly the antioxidants metallothionein-I+II (MT-I+II) and moderately the MT-III isoform. In 6-AN-injected IL-6KO mice reactive astrocytosis and recruitment of macrophages and T-lymphocytes were clearly reduced, as were BM leukopoiesis and spleen immune reaction. Expression of MT-I+II was significantly reduced while MT-III was increased. Oxidative stress, as determined by measuring nitrated tyrosine and malondialdehyde, was increased by 6-AN to a greater extent in IL-6KO mice. The blood-brain barrier to albumin was only disrupted in 6-AN-injected normal mice, which likely is due to the substantial migration of blood-derived inflammatory cells into the CNS. The present results demonstrate that inflammation in CNS is clearly reduced during IL-6 deficiency and this effect is likely due to significant inhibition of BM leukopoiesis. We also show that IL-6 deficiency reduces the levels of neuroprotective antioxidants MT-I+II followed by an increased oxidative stress during CNS inflammation.
authors.affiliation: Department of Medical Anatomy, University of Copenhagen, Copenhagen, Denmark. M.Penkowa@mai.ku.dk
authors.forename: M
authors.initials: M
authors.lastname: Penkowa
authors.forename: J
authors.initials: J
authors.lastname: Hidalgo
mesh_terms: D015120:6-Aminonicotinamide / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006410:Hematopoiesis / Q000187:drug effects / Q000276:immunology; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008315:Malondialdehyde / Q000276:immunology / Q000378:metabolism; D008668:Metallothionein / Q000096:biosynthesis*; D000090023:Metallothionein 3; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020033:Protein Isoforms / Q000096:biosynthesis; D012709:Serum Albumin / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012709:Serum Albumin; D015120:6-Aminonicotinamide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D008668:Metallothionein