Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice.
In order to determine the role of the neuropoietic cytokine interleukin-6 (IL-6) during the first 3 weeks after a focal brain injury, we examined the inflammatory response, oxidative stress and neuronal survival in normal and interleukin-6-deficient (knockout, IL-6KO) mice subjected to a cortical freeze lesion. In normal mice, the brain injury was followed by reactive astrogliosis and recruitment of macrophages from 1 day postlesion (dpl), peaking at 3-10 dpl, and by 20 dpl the transient immunoreactions were decreased, and a glial scar was present. In IL-6KO mice, the reactive astrogliosis and recruitment of macrophages were decreased throughout the experimental period. The expression of the antioxidant and anti-apoptotic factors metallothionein I+II (MT-I+II) was increased prominently by the freeze lesion, but this response was significantly reduced in the IL-6 KO mice. By contrast, the expression of the antioxidants Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-SOD, and catalase remained unaffected by the IL-6 deficiency. The lesioned mice showed increased oxidative stress, as judged by malondialdehyde (MDA) and nitrotyrosine (NITT) levels and by formation of inducible nitric oxide synthase (iNOS). IL-6KO mice showed higher levels of MDA, NITT, and iNOS than did normal mice. Concomitantly, in IL-6KO mice the number of apoptotic neurons was significantly increased as judged by TUNEL staining, and regeneration of the tissue was delayed relative to normal mice. The changes in neuronal tissue damage and in brain regeneration observed in IL-6KO mice are likely caused by the IL-6-dependent decrease in MT-I+II expression, indicating IL-6 and MT-I+II as neuroprotective factors during brain injury.
Penkowa
M
M
Institute of Medical Anatomy, Section C, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Giralt
M
M
Carrasco
J
J
Hadberg
H
H
Hidalgo
J
J
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001253:Astrocytes / Q000473:pathology; D001921:Brain / Q000276:immunology / Q000473:pathology; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009416:Nerve Regeneration / Q000276:immunology; D009474:Neurons / Q000201:enzymology / Q000276:immunology; D018384:Oxidative Stress / Q000276:immunology; D013482:Superoxide Dismutase / Q000378:metabolism
D015850:Interleukin-6; D008668:Metallothionein; D002374:Catalase; D013482:Superoxide Dismutase