Reciprocal actions of interleukin‐6 and brain‐derived neurotrophic factor on rat and mouse primary sensory neurons

Murphy, Patricia; Borthwick, Lee A.; Altares, M.; Gauldie, Jack; Kaplan, David R.; Richardson, P. M.

doi:10.1046/j.1460-9568.2000.00074.x

Cited by 103 publications

(62 citation statements)

References 45 publications

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“…This could be attributed to upregulation of overlapping functions with other neuropoietic cytokine receptors mediated by the common cytokine receptor subunit gp130. Indeed, IL-6 plays roles in neuronal survival and differentiation (März et al, 1997;Thier et al, 1999;Murphy et al, 2000) and Il6 gene deletion does not induce neuronal death (Cafferty et al, 2004). Consistent with redundancy, mice lacking individual members of IL-6 cytokine family display only mild phenotypes, as also observed in the present work, while animals lacking gp130 are not viable (Betz et al, 1998).…”

supporting

confidence: 87%

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Pieraut¹,

Lucas²,

Sangari³

et al. 2011

J. Neurosci.

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The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6 Ϫ/Ϫ mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6 Ϫ/Ϫ dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.

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supporting

confidence: 87%

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Pieraut¹,

Lucas²,

Sangari³

et al. 2011

J. Neurosci.

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“…One the other hand, this would not exclude the possibility that the electrophysiological changes ascribed to TNF-␣ contribute to synthesis of other survival-promoting factors such as BDNF. Recently, it has been described that the neuroprotective actions of interleukin-6, another proinflammatory cytokine that can influence neurotransmitter-operated ion currents (Qiu et al, 1995), on embryonic sensory neurons are mediated through a mechanism requiring endogenous BDNF (Murphy et al, 2000). Exogenously applied BDNF has been shown previously to prevent secondary RGC loss in our experimental paradigm .…”

Section: Discussionmentioning

confidence: 72%

Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

Diem¹,

Meyer²,

Weishaupt³

et al. 2001

J. Neurosci.

132

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Tumor-necrosis-factor-␣ (TNF-␣) prevented secondary death of retinal ganglion cells (RGCs) after axotomy of the optic nerve in vivo. This RGC rescue was confirmed in vitro in a mixed retinal culture model. In accordance with our previous findings, TNF-␣ decreased outward potassium currents in RGCs. Antagonism of the TNF-␣-induced decrease in outward potassium currents with the potassium channel opener minoxidilsulfate (as verified by electrophysiology) abolished neuroprotection. Western blot analysis revealed an upregulation of phospho-Akt as a consequence of TNF-␣-induced potassium current reduction. Inhibition of the phosphatidylinositol 3-kinase-Akt pathway with wortmannin decreased TNF-␣-promoted RGC survival. These data point to a functionally relevant cytokine-dependent neuroprotective signaling cascade in adult CNS neurons.

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“…Elevated levels of cytokine protein and mRNA (including IL-6) have been detected in embryonic serum and brain after MIA (Fidel et al, 1994;Cai et al, 2000;Urakubo et al, 2001;Gayle et al, 2004;Paintlia et al, 2004;Gilmore et al, 2005;Ashdown et al, 2006;Beloosesky et al, 2006;Meyer et al, 2006;Xu et al, 2006). IL-6 can regulate brain-derived neurotrophic factor (BDNF) expression (Murphy et al, 2000), and a decrease in BDNF is found in embryos and placentas 24 h after poly(I:C) administration (Gilmore et al, 2005). Thus, although the pleiotropic nature of IL-6 makes it difficult to predict the precise mechanism of action in the brain, many plausible pathways exist.…”

Section: Discussionmentioning

confidence: 99%

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

et al. 2007

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Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.Key words: schizophrenia; autism; cytokine; poly(I:C); maternal immune activation; IL-6; influenza IntroductionBirth in winter or spring months is an accepted risk factor for schizophrenia, and the preponderance of evidence suggests that the prevalence of influenza in winter months is responsible (Tochigi et al., 2004). Over 25 studies have analyzed schizophrenia incidence after influenza epidemics, and the majority have found an increased incidence among exposed offspring. More recently, Brown and colleagues (Brown and Susser, 2002;Brown et al., 2004;Brown, 2006) examined the medical records of Ͼ12,000 pregnant women and found that second-trimester respiratory infection increases the risk for schizophrenia in the offspring threefold to sevenfold. Because of the high prevalence of influenza infection, they estimate that 14 -21% of schizophrenia cases are caused by maternal infection. These findings are also supported by an association between elevated cytokines or antiinfluenza antibodies in maternal serum and schizophrenia in the offspring (Brown et al., 2004). Maternal infection may also play a role in the pathogenesis of autism (Patterson, 2002). These links are even more remarkable considering that the epidemiological studies are unable to screen for susceptibility genotype. Because of the strong genetic component in autism and schizophrenia, it is likely that only genetically susceptible individuals who were exposed to maternal infection would develop the disorder, suggesting that the risk associated with maternal infect...

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Reciprocal actions of interleukin‐6 and brain‐derived neurotrophic factor on rat and mouse primary sensory neurons

Cited by 103 publications

References 45 publications

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Reduction of Potassium Currents and Phosphatidylinositol 3-Kinase-Dependent Akt Phosphorylation by Tumor Necrosis Factor-α Rescues Axotomized Retinal Ganglion Cells from Retrograde Cell DeathIn Vivo

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

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