Interleukin-6 mRNA expression by cortical neurons in culture: Evidence for neuronal sources of interleukin-6 production in the brain

Ringheim, Garth E.; Burgher, Kendra L.; Heroux, Jeffrey A.

doi:10.1016/0165-5728(95)00134-4

Cited by 143 publications

(77 citation statements)

References 31 publications

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“…Interleukin-1, TNFs, and depolarization have all been reported to stimulate IL-6 expression in cortical and sensory neurons (Ringheim et al, 1995;Sallmann et al, 2000). Sallmann et al (2000) also found that depolarization-induced IL-6 transcription depends on calcium and calcium calmodulin-dependent kinases, suggesting that NMDA receptor activation may contribute to IL-6 mRNA increases after SCI.…”

Section: The Effect Of the Nmda Receptor Noncompetitive Antagonist Mmentioning

confidence: 99%

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

Nešić

Švrakić

et al. 2002

J of Neuroscience Research

102

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Spinal cord injury (SCI)-induced neurodegeneration leads to irreversible and devastating motor and sensory dysfunction. Post-traumatic outcomes are determined by events occurring during the first 24 hours after SCI. An increase in extracellular glutamate concentration to neurotoxic levels is one of the earliest events after SCI. We used Affymetrix DNA oligonucleotide microarrays (with 1,322 DNA probes) analysis to measure gene expression in order to test the hypothesis that SCI-induced N-methyl-D-aspartate (NMDA) receptor activation triggers significant postinjury transcriptional changes. Here we report that SCI, 1 hour after trauma, induced change in mRNA levels of 165 genes and expression sequence tags (ESTs). SCI affected mRNA levels of those genes that regulate predominantly transcription factors, inflammation, cell survival, and membrane excitability. We also report that NMDA receptor inhibition (with -(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate ) reversed the effect of SCI on about 50% of the SCI-affected mRNAs. Especially interesting is the finding that NMDA receptor activation participates in the up-regulation of inflammatory factors. Therefore, SCI-induced NMDA receptor activation is one of the dominant, early signals after trauma that leads to changes in mRNA levels of a number of genes relevant to recovery processes. The majority of MK-801 effects on the SCI-induced mRNA changes reported here are novel. Additionally, we found that the MK-801 treatment also changed the mRNA levels of 168 genes and ESTs that had not been affected by SCI alone, and that some of their gene products could have harmful effects on SCI outcome.

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Section: The Effect Of the Nmda Receptor Noncompetitive Antagonist Mmentioning

confidence: 99%

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

Nešić

Švrakić

et al. 2002

J of Neuroscience Research

102

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“…Although its exact source remains to be established, elevated levels of IL-6 have been detected in the CSF following brain infections, injuries, trauma, and neurodegenerative diseases (Laurenzi et al, 1990;Woodroofe et al, 1991;Yan et al, 1992;Campbell et al, 1993;Taupin et al, 1993). Several studies have shown that astrocytes (Benveniste et al, 1990), microglial cells (Woodroofe et al, 1991;Sawada et al, 1992), and neurons (Ringheim et al, 1995) are capable of synthesizing IL-6 after different immunogenic stimuli. A possible role of centrally produced IL-6 might be to support the local immune reaction by repressing neurotoxic inflammatory processes, increasing antibody secretion, inducing gliosis, and stimulating cells that form the blood-brain barrier (astrocytes and microglial and endothelial cells) to promote leukocyte infiltration (Schöbitz et al, 1994).…”

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confidence: 99%

Regulation of the Genes Encoding Interleukin‐6, Its Receptor, and gp130 in the Rat Brain in Response to the Immune Activator Lipopolysaccharide and the Proinflammatory Cytokine Interleukin‐1β

Vallières

Rivest

1997

Journal of Neurochemistry

289

181

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Interleukin-6 (IL-6) is a pleiotropic cytokirie believed to play key roles in the neuroimmune interactions. This molecule may act on the nervous system by interacting with its specific receptor subunit (IL-6R) and the signal transducer gp130. The purposes of the present study were to describe the central distribution of IL-6, IL-6R, and gpl3O mRNAs under basal conditions and to verify the influence of the immune activator lipopolysaccharide (LPS) and the proinflammatory cytokine interleukm-1/3 (IL-1/3) on the expression of IL-6 and its related genes throughout the rat brain. Rats were killed at multiple times after intraperitoneal injection of the bacterial endotoxin and intravenous administration of the recombinant rat IL-1/3 (rrlL-1ß), and their brains were cut into 30-~zmcoronal sections from the olfactory bulb to the end of the medulla. Each transcript was localized by in situ hybridization histochemistry using 35S-labeled rat riboprobes. The results show that IL-6 mRNA was undetectable in the brain under basal conditions and following the injection of rrlL-1/3. Injection of LPS rapidly stimulated transcription of this gene in the choroid plexus and the sensorial circumventricular organs (CVOs), including the organum vasculosum Iaminae terminalis (OVLT), subfornical organ, median eminence, and area postrema. Conversely, IL-6R and gpl3O mRNAs were heterogeneously distributed throughout the brain under basal conditions. The injection of LPS stimulated the biosynthesis of IL-6R in the CVOs, medial preoptic area, bed nucleus stria terminalis, central nucleus of the amygdala, hippocampus, hypothalamic paraventricular nucleus, cerebral cortex, and blood vessels. Increased levels of IL-6R mRNA were also observed in the microvasculature following rrlL-1/3 injection. Finally, gp130 mRNA expression was increased in the OVLT and throughout the endothelium of brain capillaries of LPS-treated rats but remained unchanged after administration of rrIL-1/3. These results demonstrate that expression of the genes encoding IL-6, IL-6R, and gpl3O can be up-regulated in selective regions of the brain in response to the bacterial endotoxin LPS and the proinflammatory cytokine IL-1/3 (only for IL-6R expression). This fine genetic regulation might be of great importance in the neuroimmune interplay and provides the evidence that sensorial CVOs and microvasculature are in a privileged position to mediate the action of IL-6 of central and/or systemic origin in the brain of immune-challenged animals. Key Words: Brain-c-fosCircumventricular organs-Cytokines-gpl 30-Immune response-In situ hybridization -Interleukin-1 -Interleukin-6-Lipopolysaccharide-mRNA-Neuroimmunology-Rat-Receptor.

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“…Examples of peripheral sources are hepatocytes (Panesar et al, 1999;Saad et al, 1995), skin fibroblasts (Helfgott et al, 1987;May et al, 1988) and mesangial cells of the kidney (Rugo et al, 1992). Cells within or associated to the brain that have been shown to produce IL-6 are brain endothelial cells (Reyes et al, 1999;Verma et al, 2006), astrocytes, microglia, and neurons (Benveniste et al, 1990;Beurel and Jope, 2009;Ringheim et al, 1995;Sawada et al, 1992;Vallieres and Rivest, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 is synthesized and secreted by monocytes/macrophages (Bauer et al, 1988;Callery et al, 1992;May et al, 1988;Northoff et al, 1987), fibroblasts (Helfgott et al, 1987;May et al, 1988), brain endothelial cells (Kakumu et al, 1992;Reyes et al, 1999;Verma et al, 2006), muscle cells (Andreasen et al, 2011), and hepatocytes (Panesar et al, 1999;Saad et al, 1995) following challenge with bacterial endotoxin. IL-6 has also been shown to be produced by astrocytes (Benveniste et al, 1990;Beurel and Jope, 2009), microglial cells (Sawada et al, 1992;Woodroofe et al, 1991), adipocytes (Flower et al, 2003), and neurons (Ringheim et al, 1995;Vallieres and Rivest, 1997) following different stimuli. IL-6 is thus synthesized by several different cells, however it has been difficult to determine the contribution of a specific cell type in vivo.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

Hamzic

Tang

Eskilsson

et al. 2013

Brain, Behavior, and Immunity

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KO background, but with intact IL-6 production in cells of hematopoietic origin, only showed a minor elevation of the body temperature after peripheral LPS injection. While they displayed significantly elevated levels of IL-6 both in plasma and CSF compared with control mice, the increase was modest compared with that seen in LPS injected mice on a WT background, the latter being approximately 20 times larger in magnitude. These results suggest that IL-6 of non-hematopoietic origin is the main source of IL-6 in LPS-induced fever, and that IL-6 produced by hematopoietic cells only plays a minor role.Hamzic et al., page 3

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Interleukin-6 mRNA expression by cortical neurons in culture: Evidence for neuronal sources of interleukin-6 production in the brain

Cited by 143 publications

References 31 publications

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

DNA microarray analysis of the contused spinal cord: Effect of NMDA receptor inhibition

Regulation of the Genes Encoding Interleukin‐6, Its Receptor, and gp130 in the Rat Brain in Response to the Immune Activator Lipopolysaccharide and the Proinflammatory Cytokine Interleukin‐1β

Interleukin-6 primarily produced by non-hematopoietic cells mediates the lipopolysaccharide-induced febrile response

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