Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice

Abstract

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. GLIA 32:271–285, 2000. © 2000 Wiley‐Liss, Inc.

Involvement of Pro- and Anti-Inflammatory Cytokines and Chemokines in the Pathophysiology of Traumatic Brain Injury

“…37 Concordantly, in experiments using the same injury model mice deficient for IL-6 exhibited increased oxidative stress, decreased cell survival, and delayed wound healing, 38 indicating that IL-6 is required for repair.…”

EP2 Receptor Signaling Pathways Regulate Classical Activation of Microglia

“…Mice with IL-6 deficiency were fully resistant to experimental allergic encephalomyelitis, and IL-6 is proposed to be a therapeutic target for autoimmune diseases (49). However, in traumatic brain injury, mice deficient for IL-6 showed increased oxidative stress, decreased cell survival, and delayed wound healing, indicating that IL-6 might also be protective (50). Here, we show that PGE 2 and EP2 activation by butaprost exacerbates the induction of COX-2, iNOS, and IL-6, which should promote inflammation caused by microglial activation, in classically activated microglia.…”

Temporal Profile of Cerebrospinal Fluid, Plasma, and Brain Interleukin-6 After Normothermic Fluid-Percussion Brain Injury: Effect of Secondary Hypoxia

“…As previously discussed, IL-6 has a multitude of actions after brain injury ranging from neuroprotective (Nijsten et al, 1987;Maeda et al, 1994;Carlson et al, 1999) to neurotoxic (Campbell et al, 1993;Chiang et al, 1994;Tilg et al, 1997;Loddick et al, 1998;Penkowa et al, 1999Penkowa et al, , 2000Penkowa et al, , 2003. In this regard, the duality of the inflammatory response to TBI in terms of potential therapeutic targets has been previously recognized (Lenzlinger et al, 2001;Morganti-Kossmann et al, 2007;Suzuki et al, 2009).…”