Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

Byts, Nadiya; Samoylenko, Anatoly; Woldt, Helge; Ehrenreich, Hannelore; Sirén, Anna‐Leena

doi:10.1007/s11064-006-9149-0

Cited by 18 publications

(21 citation statements)

References 58 publications

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“…We have previously shown the involvement of autocrine positive feedback loops in the activation of BMEC by bacterial cell wall components (14). Other authors have reported an induction of proinflammatory cytokines by Tpo in an endothelial cell line (8) as well as activation of ERK1/2 signaling in astrocytes (6). Taken together, these results suggest that production of Tpo by BMEC could provide proinflammatory stimuli to the endothelium itself as well as to adjacent asctrocytes, thus modulating the local inflammatory response in meningitis.…”

Section: Discussionsupporting

confidence: 58%

Thrombopoietin Contributes to Neuronal Damage in Experimental Bacterial Meningitis

Hoffmann

Rung

et al. 2011

Infect Immun

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Thrombopoietin (Tpo), which primarily regulates megakaryopoiesis, and its receptor (c-Mpl) are expressed in the brain, where Tpo exhibits proapototic effects on neurons. In the present study, we investigated the implication of Tpo in experimental pneumococcal meningitis. Following intrathecal infection with the encapsulated Streptococcus pneumoniae strain D39, we observed upregulation of Tpo mRNA expression at 12 h and 24 h in brain homogenates of wild-type C57BL/6 mice. c-Mpl mRNA expression was upregulated at 12 h and returned to baseline at 24 h. Compared to wild-type mice, mutants with homozygous Tpo receptor ablation (c-Mpl ؊/؊ ) displayed reduced microglial activation and neuronal apoptosis in the dentate gyrus. Concentrations of bacteria in blood or cerebrospinal fluid (CSF), as well as CSF pleocytosis, were not significantly different between wild-type and c-Mpl ؊/؊ mice. In human postmortem brain, Tpo protein was colocalized to macrophages during encephalitis. In murine primary microglia and RAW264.7 macrophages, upregulation of Tpo mRNA was induced by D39-conditioned medium but not by bacterial lipopeptide or by medium conditioned by pneumococcal mutants defective in hydrogen peroxide formation (⌬spxB) or pneumolysin (⌬pln). We conclude that Tpo acts as a mediator of neuronal damage in bacterial meningitis.

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Section: Discussionsupporting

confidence: 58%

Thrombopoietin Contributes to Neuronal Damage in Experimental Bacterial Meningitis

Hoffmann

Rung

et al. 2011

Infect Immun

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“…In rat hippocampal neurons, THPO induced cell death and the induction of pro-apoptotic proteins most likely contributed to this effect [72]. Studies in PC12 cells indicated that THPO decreases neuronal survival by suppressing NGF-induced ERK activity [73].…”

Section: Discussionmentioning

confidence: 99%

Adjunctive Dexamethasone Affects the Expression of Genes Related to Inflammation, Neurogenesis and Apoptosis in Infant Rat Pneumococcal Meningitis

et al. 2011

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Streptococcus pneumoniae is the most common pathogen causing non-epidemic bacterial meningitis worldwide. The immune response and inflammatory processes contribute to the pathophysiology. Hence, the anti-inflammatory dexamethasone is advocated as adjuvant treatment although its clinical efficacy remains a question at issue. In experimental models of pneumococcal meningitis, dexamethasone increased neuronal damage in the dentate gyrus. Here, we investigated expressional changes in the hippocampus and cortex at 72 h after infection when dexamethasone was given to infant rats with pneumococcal meningitis. Nursing Wistar rats were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis or were sham-infected with pyrogen-free saline. Besides antibiotics, animals were either treated with dexamethasone or saline. Expressional changes were assessed by the use of GeneChip® Rat Exon 1.0 ST Arrays and quantitative real-time PCR. Protein levels of brain-derived neurotrophic factor, cytokines and chemokines were evaluated in immunoassays using Luminex xMAP® technology. In infected animals, 213 and 264 genes were significantly regulated by dexamethasone in the hippocampus and cortex respectively. Separately for the cortex and the hippocampus, Gene Ontology analysis identified clusters of biological processes which were assigned to the predefined categories “inflammation”, “growth”, “apoptosis” and others. Dexamethasone affected the expression of genes and protein levels of chemokines reflecting diminished activation of microglia. Dexamethasone-induced changes of genes related to apoptosis suggest the downregulation of the Akt-survival pathway and the induction of caspase-independent apoptosis. Signalling of pro-neurogenic pathways such as transforming growth factor pathway was reduced by dexamethasone resulting in a lack of pro-survival triggers. The anti-inflammatory properties of dexamethasone were observed on gene and protein level in experimental pneumococcal meningitis. Further dexamethasone-induced expressional changes reflect an increase of pro-apoptotic signals and a decrease of pro-neurogenic processes. The findings may help to identify potential mechanisms leading to apoptosis by dexamethasone in experimental pneumococcal meningitis.

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“…One of the few growth factors currently approved for clinical use is the granulocyte colony-stimulating factor (GCSF), routinely prescribed to treat neutropenia (low neutrophil count in the blood) [2]. In addition, GCSF can cross the blood-brain barrier, and recent experimental studies have shown that the administration of GCSF is neuroprotective both for in vitro cultured cortical neurons and in vivo focal cerebral ischemia [3][4][5][6][7]. GCSF upregulates expression of several anti-apoptotic genes, including B-cell lymphoma 2 protein (Bcl2), B-cell lymphoma-extra large protein (Bcl-xl), cellular inhibitor of apoptosis protein 2 (ciap2) and p27 [6,8] (see review by Solaroglu et al [9]).…”

Section: Introductionmentioning

confidence: 99%

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

Gomez-Smith

Qin

Zhou

et al. 2009

Cell. Mol. Life Sci.

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Granulocyte colony-stimulating factor (GCSF) is currently in clinical trials to treat neurodegenerative diseases and stroke. Here, we tested whether LIM domain only 4 protein (LMO4), a hypoxia-inducible gene that protects neurons from ischemic injury, could modulate the neuroprotective effect of GCSF. We showed that GCSF treatment acetylates and phosphorylates Stat3, activates expression of a Stat3-dependent anti-apoptotic gene, p27, and increases neuron survival from ischemic injury. LMO4 participates in Stat3 signaling in hepatocytes and associates with histone deacetylase 2 (HDAC2) in cancer cells. In the absence of LMO4, GCSF fails to rescue neurons from ischemic insults. In wild-type neurons, inhibition of HDAC promoted Stat3 acetylation and the antiapoptotic effect of GCSF. In LMO4 null cortical neurons, expression of wild-type but not HDAC-interaction-deficient LMO4 restored GCSF-induced Stat3 acetylation and p27 expression. Thus, our results indicate that LMO4 enhances GCSF-induced Stat3 signaling in neurons, in part by sequestering HDAC.

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Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

Cited by 18 publications

References 58 publications

Thrombopoietin Contributes to Neuronal Damage in Experimental Bacterial Meningitis

Thrombopoietin Contributes to Neuronal Damage in Experimental Bacterial Meningitis

Adjunctive Dexamethasone Affects the Expression of Genes Related to Inflammation, Neurogenesis and Apoptosis in Infant Rat Pneumococcal Meningitis

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

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