Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells

Haghikia, Aiden; Ladage, Kerstin; Lafenêtre, Pauline; Haghikia, Arash; Hinkerohe, Daniel; Smikalla, Dirk; Haase, Claus G.; Dermietzel, Rolf; Faustmann, Pedro M.

doi:10.1007/s11060-007-9462-8

Cited by 27 publications

(21 citation statements)

References 46 publications

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“…These data are in accordance with previous studies that reported IL-1β downregulates the expression of Cx43 in astrocyte-rich cultures2122. However, our present data differ from previous reports regarding the effects of proinflammatory cytokines on glial cells2324. Haghikia et al .…”

Section: Discussionsupporting

confidence: 88%

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Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

Watanabe

Kitajima

Yamasaki

et al. 2016

Sci Rep

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We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNγ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS.

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Section: Discussionsupporting

confidence: 88%

“…Haghikia et al . reported that TNFα inhibits the function of GJs in astrocyte/microglia co-cultures containing 5% microglia derived from rat brain23. Zhang et al .…”

Section: Discussionmentioning

confidence: 99%

Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

Watanabe

Kitajima

Yamasaki

et al. 2016

Sci Rep

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“…On analysis of a subset of our samples (20) from GBM patients and normal controls (14), we did not find a significant difference in the mean levels of circulating TNFα as measured by ELISA (data not shown). TNF-R1 is expressed by glioma tumor cell lines [43, 44] whereas TNF-R2 is expressed by some, but not all glioma cell lines [43] and shedding of both TNF-R1 and TNF-R2 by glioma cell lines has been described [45]. Microrarray analysis indicates overexpression of TNF-R1 in some GBM tumors where RNA was extracted from whole tumors [29, 46].…”

Section: Discussionmentioning

confidence: 99%

Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma

et al. 2016

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The circulating levels of soluble tumor necrosis factor receptor-1 (sTNF-R1) and sTNF-R2 are altered in numerous diseases, including several types of cancer. Correlations with the risk of progression in some cancers, as well as systemic manifestations of the disease and therapeutic side-effects, have been described. However, there is very little information on the levels of these soluble receptors in glioblastoma (GBM). Here, we report on an exploratory retrospective study of the levels of sTNF-Rs in the vascular circulation of patients with GBM. Banked samples were obtained from 112 GBM patients (66 untreated, newly-diagnosed patients and 46 with recurrent disease) from two institutions. The levels of sTNF-R1 in the plasma were significantly lower in patients with newly-diagnosed or recurrent GBM than apparently healthy individuals and correlated with the intensity of expression of TNF-R1 on the tumor-associated endothelial cells (ECs) in the corresponding biopsies. Elevated levels of sTNF-R1 in patients with recurrent, but not newly-diagnosed GBM, were significantly associated with a shorter survival, independent of age (p=0.02) or steroid medication. In contrast, the levels of circulating sTNF-R2 were significantly higher in recurrent GBM than healthy individuals and there was no significant correlation with expression of TNF-R2 on the tumor-associated ECs or survival time. The results indicate that larger, prospective studies are warranted to determine the predictive value of the levels of sTNF-R1 in patients with recurrent GBM and the factors that regulate the levels of sTNF-Rs in the circulation in GBM patients.

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“…In addition, in astrocyte cultures not devoid of microglia, LPS or pro-inflammatory cytokines reduce astroglial coupling via nitric oxide synthase (NOS) induction and a p38 kinase-dependent pathway (40, 91, 139, 164, 235, 408). Both the IL-1 β and TNF- α effects on gap junctions occur as early as 2 h after application (139, 408). Because this latency is close to the half-life of Cx43 (197), the action may be due to block of synthesis or increase in degradation of Cx.…”

Section: Glial Cells and Their Implication In Neurodegenerative Diseasesmentioning

confidence: 99%

Modulation of Brain Hemichannels and Gap Junction Channels by Pro-Inflammatory Agents and Their Possible Role in Neurodegeneration

Orellana

Saéz

Shoji

et al. 2009

Antioxidants & Redox Signaling

205

190

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In normal brain, neurons, astrocytes, and oligodendrocytes, the most abundant and active cells express pannexins and connexins, protein subunits of two families forming membrane channels. Most available evidence indicates that in mammals endogenously expressed pannexins form only hemichannels and connexins form both gap junction channels and hemichannels. Whereas gap junction channels connect the cytoplasm of contacting cells and coordinate electric and metabolic activity, hemichannels communicate the intra- and extracellular compartments and serve as a diffusional pathway for ions and small molecules. A subthreshold stimulation by acute pathological threatening conditions (e.g., global ischemia subthreshold for cell death) enhances neuronal Cx36 and glial Cx43 hemichannel activity, favoring ATP release and generation of preconditioning. If the stimulus is sufficiently deleterious, microglia become overactivated and release bioactive molecules that increase the activity of hemichannels and reduce gap junctional communication in astroglial networks, depriving neurons of astrocytic protective functions, and further reducing neuronal viability. Continuous glial activation triggered by low levels of anomalous proteins expressed in several neurodegenerative diseases induce glial hemichannel and gap junction channel disorders similar to those of acute inflammatory responses triggered by ischemia or infectious diseases. These changes are likely to occur in diverse cell types of the CNS and contribute to neurodegeneration during inflammatory process. Antiox. Redox Signal. 11, 369–399.

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Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells

Cited by 27 publications

References 46 publications

Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation

Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma

Modulation of Brain Hemichannels and Gap Junction Channels by Pro-Inflammatory Agents and Their Possible Role in Neurodegeneration

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