Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice

Penkowa, Milena; Moos, Torben; Carrasco, Javier; Hadberg, Hanne; Molinero, Amalia; Bluethmann, Horst; Hidalgo, Juan

doi:10.1002/(sici)1098-1136(19990215)25:4<343::aid-glia4>3.0.co;2-v

Cited by 176 publications

(102 citation statements)

References 70 publications

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“…We also evaluated the expression level of IL-6, a pleiotropic cytokine that has been shown to be neuroprotective in several types of brain injury including stroke and TBI (Morganti-Kossmann et al, 2002;Suzuki et al, 2009;Ziebell and MorgantiKossmann, 2010). Interleukin-6 may actually attenuate oxidative damage, exert antiapoptotic actions, and participate in brain repair processes (Penkowa et al, 1999;Stahel et al, 2000). We found that LPS-preconditioned mice at 5 days interval had increased IL-6 mRNA expression after TBI compared with saline-treated mice, supporting the hypothesis that stimulation of production of neuroprotective factors (IFNb and IL-6) is part of the mechanisms by which LPS preconditioning confers neuroprotection.…”

Section: Discussionsupporting

confidence: 69%

Long-lasting protection in brain trauma by endotoxin preconditioning

Longhi

Gesuete

Perego

et al. 2011

J Cereb Blood Flow Metab

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We investigated the occurrence of endotoxin (lipopolysaccharide, LPS) preconditioning in traumatic brain injury (TBI), evaluating the time window of LPS-induced protection, its persistence, and the associated molecular mechanisms. Mice received 0.1 mg/kg LPS or saline intraperitoneally and subsequently TBI (by controlled cortical impact brain injury) at various time intervals. Mice receiving LPS 3, 5, or 7 days before TBI showed attenuated motor deficits at 1 week after injury compared with mice receiving saline. Those receiving LPS 5 days before injury had also a reduced contusion volume (7.9±1.3 versus 12±2.3 mm 3 ) and decreased cell death. One month after injury, the protective effect of LPS on contusion volume (14.5 ± 1.2 versus 18.2 ± 1.2 mm 3 ) and neurologic function was still present. Traumatic brain injury increased glial fibrillary acidic protein, CD11b, CD68, tumor necrosis factor-a, interleukin (IL)-10, and IL-6 mRNA expression 24 hours after injury. Lipopolysaccharide administered 5 (but not 9) days before injury increased the expression of CD11b (233%) and of interferon b (500%) in uninjured mice, while it reduced the expression of CD68 (by 46%) and increased that of IL-6 (by 52%) in injured mice. Lipopolysaccharide preconditioning conferred a long-lasting neuroprotection after TBI, which was associated with a modulation of microglia/macrophages activity and cytokine production.

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Section: Discussionsupporting

confidence: 69%

Long-lasting protection in brain trauma by endotoxin preconditioning

Longhi

Gesuete

Perego

et al. 2011

J Cereb Blood Flow Metab

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“…Moreover, IL-6 was also found to be neuroprotective in vivo upon cryolesion induced brain damage, as shown recently in IL-6 deficient mice (Penkowa et al 1999). However, similarly to other cytokines (MunozFernandez and Fresno 1998), Il-6 may exert both beneficial and detrimental activities in neuronal tissue depending on yet undefined factors (Campbell 1998;Gadient and Otten 1997;Merrill and Jonakait 1995).…”

mentioning

confidence: 55%

Interleukin-6 Enhances Expression of Adenosine A1 Receptor mRNA and Signaling in Cultured Rat Cortical Astrocytes and Brain Slices

Biber

2001

Neuropsychopharmacology

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The inhibitory neuromodulator adenosine is released in the brain in high concentrations under conditions of exaggerated neuronal activity such as ischemia and seizures, or electroconvulsive treatment. By inhibiting neural overactivity, adenosine counteracts seizure activity and promotes neuronal survival. Since stimulation of adenosineAdenosine, as a metabolite of ATP, nature's general energy source, has acquired early in evolution the general function of signaling and counteracting a dysbalance of energy supply and demand (Newby 1984). In the brain, adenosine acts as an inhibitory neuromodulator, which is released under conditions of neuronal activity and reduces this activity by inhibition of transmitter release and postsynaptic hyperpolarisation. Brain damage, e.g., by stroke, ischemia, and seizures leads to a pronounced increase in extracellular adenosine (for review see Rudolphi and Schubert 1996) which counteracts seizure activity (Dragunow 1988) and promotes neuronal survival (Deckert and Gleiter 1994;Picano and Abbracchio 1998;Dux et al. 1990).In addition to its role as an endogenous anticonvulsant and neuroprotective agent, adenosine is now recognized as an important regulator of sleep and wakefulness (for review see Porkka-Heiskanen 1999 (van Calker et al. 1978(van Calker et al. , 1979, but more recent findings have revealed coupling of adenosine receptors to other signaling systems including the phosphoinositol system, potassium, and calcium channels (for review see Fredholm et al. 1994;Ralevic and Burnstock 1998). Adenosine mediates neuroprotection by inhibiting presynaptically the release of several neurotransmitters including the excitatory neurotransmitter glutamate (Ribeiro 1995). Postsynaptically, adenosine increases conductances of various K ϩ -and Cl Ϫ -channels, which hyperpolarize the membrane potential and counteract a transmitter induced depolarisation with a subsequent reduction of Ca 2 ϩ -influx and stabilization of the Mg 2 ϩ blockage of NMDA receptors (Rudolphi et al. 1992a,b;Rudolphi and Schubert 1996). Most, if not all, of these actions of adenosine are mediated via the adenosine A 1 receptor, whereas the role of the other adenosine receptor subtype in neuroprotection is less clear (Schubert et al. 1997;Abbracchio and Cattabeni 1999;Heurteaux et al. 1995). Accordingly, upregulation of adenosine A 1 receptors by chronic treatment with A 1 -antagonists increases the neuroprotective effect of adenosine (Sutherland et al. 1991; Rudolphi et al. 1992a,b).Upregulation of adenosine A1-receptors is also observed after treatments that exert antidepressive effects in humans such as seizures and electroconvulsive treatment (ECT) (Newman et al. 1984;Gleiter et al. 1989;Angelatou et al..1993;Pagonopoulou et al. 1993), REM sleep deprivation (Yanik and Radulovacki 1987), and chronic treatment with carbamazepine (Daval et al. 1989;Biber et al. 1999;van Calker et al. 2000). While the upregulation by carbamazepine of adenosine A 1 receptors is readily comprehensible from carbamazepine's selective antag...

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“…These studies, as well as those carried out in IL-6 KO mice (10,51), demonstrated that IL-6 is a major cytokine regarding the control of MT isoforms in the CNS. In the present report, we have examined whether the astrocyte-targeted expression of TNF-␣, which causes a chronic-progressive neurological disorder, is associated with altered expression of the MT isoforms.…”

Section: Introductionmentioning

confidence: 76%

“…Other sections were preincubated in 10% goat serum (In Vitro, DK, code 04009-1B) in TBS/Nonidet with 0.01% TBS/Nonidet for 30 min at room temperature, followed by incubation with blocking solutions A ϩ B from the HistoMouse-SP kit to quench endogenous mouse IgG (Zymed Lab. Inc., code 95-9544), followed by incubation overnight for double immunofluorescence stainings with the following primary antibodies: mouse anti-horse MT-I ϩ II (IgG) 1:50 (Dakopatts, DK, code M0639), and rabbit anti-MT-III (IgG) 1:1000 (9,11,51). These primary antibodies were detected using goat anti-mouse IgG conjugated with coumarin/ AMCA 1:50 (Dakopatts, DK, code W0477) and goat anti-rabbit IgG conjugated with Texas Red 1:50 (Jackson ImmunoResearch Lab.…”

Section: Immunofluorescence Histochemistrymentioning

confidence: 99%

Metallothioneins Are Upregulated in Symptomatic Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor-α

Carrasco

Giralt

Penkowa

et al. 2000

Experimental Neurology

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Transgenic mice expressing TNF-␣ under the regulatory control of the GFAP gene promoter (GFAP-TNF␣ mice) exhibit a unique, late-onset chronic-progressive neurological disorder with meningoencephalomyelitis, neurodegeneration, and demyelination with paralysis. Here we show that the metallothionein-I ؉ II (MT-I ؉ II) isoforms were dramatically upregulated in the brain of symptomatic but not presymptomatic GFAP-TNF␣ mice despite TNF-␣ expression being present in both cases. In situ hybridization analysis for MT-I RNA and radioimmunoassay results for MT-I ؉ II protein revealed that the induction was observed in the cerebellum but not in other brain areas. Increased MT-I RNA levels occurred in the Purkinje and granular neuronal layers of the cerebellum but also in the molecular layer. Reactive astrocytes, activated rod-like microglia, and macrophages, but not the infiltrating lymphocytes, were identified as the cellular sources of the MT-I ؉ II proteins. In situ hybridization for MT-III RNA revealed a modest increase in the white matter of the cerebellum, which was confirmed by immunocytochemistry. MT-III immunoreactivity was present in cells which were mainly round or amoeboid monocytes/macrophages. The pattern of expression of the different MT isoforms in the GFAP-TNF␣ mice differed substantially from that described previously in GFAP-IL6 mice, demonstrating unique effects associated with the expression of each cytokine. The results suggest that the MT expression in the CNS reflects the inflammatory response and associated damage rather than a direct role of the TNF-␣ in their regulation and support a major role of these proteins during CNS injury.

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Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice

Cited by 176 publications

References 70 publications

Long-lasting protection in brain trauma by endotoxin preconditioning

Long-lasting protection in brain trauma by endotoxin preconditioning

Interleukin-6 Enhances Expression of Adenosine A1 Receptor mRNA and Signaling in Cultured Rat Cortical Astrocytes and Brain Slices

Metallothioneins Are Upregulated in Symptomatic Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor-α

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