M. Penkowa et al., Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice, GLIA, 32(3), 2000, pp. 271-285
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 fr
eeze lesion. In normal mice, the brain injury was followed by reactive astr
ogliosis and recruitment of macrophages from I day postlesion (dpl), peakin
g 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 peri
od. The expression of the antioxidant and anti-apoptotic factors metallothi
onein I+II (MT-I+II) was increased prominently by the freeze lesion, but th
is 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 th
an did normal mice. Concomitantly, in IL-6KO mice the number of apoptotic n
eurons was significantly increased as judged by TUNEL staining, and regener
ation of the tissue was delayed relative to normal mice. The changes in neu
ronal tissue damage and in brain regeneration observed in IL-6KO mice are l
ikely caused by the IL-6-dependent decrease in MT-I+II expression, indicati
ng IL-6 and MT-I+II as neuroprotective factors during brain injury. (C) 200
0 Wiley-Liss, Inc.