Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Park, Soo Jung; Lee, Jee Hoon; Kim, Hee Young; Choi, Youn Hee; Park, Jung Sup; Suh, Young Ho; Park, Sang Myun; Joe, Eun Hye; Jou, Ilo

doi:10.4049/jimmunol.1101600

Cited by 38 publications

(26 citation statements)

References 63 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, STAT6 is a key component of the intracellular pathway downstream of IL-4 signaling, and the IL-4-STAT6 axis is likely to orchestrate various phenotypes of alternatively activated astrocytes, including the expression of specific phenotypic markers and neuroprotective molecules. A recent study found that phosphorylation of STAT6 was induced by IL-4 in astrocytes (77), which concurs with our finding that STAT6 was phosphorylated in IL-4-activated astrocytes. In addition, we present evidence that LCN2 targets IL-4-STAT6 signaling to inhibit the alternative activation of astrocytes (see later discussion).…”

Section: Discussionsupporting

confidence: 82%

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

Jang

Kim

Lee

et al. 2013

The Journal of Immunology

182

157

View full text Add to dashboard Cite

Astrocytes provide structural and functional support for neurons, as well as display neurotoxic or neuroprotective phenotypes depending upon the presence of an immune or inflammatory microenvironment. This study was undertaken to characterize multiple phenotypes of activated astrocytes and to investigate the regulatory mechanisms involved. We report that activated astrocytes in culture exhibit two functional phenotypes with respect to pro- or anti-inflammatory gene expression, glial fibrillary acidic protein expression, and neurotoxic or neuroprotective activities. The two distinct functional phenotypes of astrocytes were also demonstrated in a mouse neuroinflammation model, which showed pro- or anti-inflammatory gene expression in astrocytes following challenge with classical or alternative activation stimuli; similar results were obtained in the absence of microglia. Subsequent studies involving recombinant lipocalin-2 (LCN2) protein treatment or Lcn2-deficient mice indicated that the pro- or anti-inflammatory functionally polarized phenotypes of astrocytes and their intracellular signaling pathway were critically regulated by LCN2 under in vitro and in vivo conditions. Astrocyte-derived LCN2 promoted classical proinflammatory activation of astrocytes but inhibited IL-4–STAT6 signaling, a canonical pathway involved in alternative anti-inflammatory activation. Our results suggest that the secreted protein LCN2 is an autocrine modulator of the functional polarization of astrocytes in the presence of immune or inflammatory stimuli and that LCN2 could be targeted therapeutically to dampen proinflammatory astrocytic activation and related pathologies in the CNS.

show abstract

Section: Discussionsupporting

confidence: 82%

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

Jang

Kim

Lee

et al. 2013

The Journal of Immunology

182

157

View full text Add to dashboard Cite

show abstract

“…We have reported that, in brain astrocytes, H 2 O 2 administration results in activation of signaling pathways by inducing protein phosphorylation via lipid rafts [33, 36, 37]. To ascertain whether lipid rafts are involved in H 2 O 2 -induced phosphorylation of STAT-6 in T cells, we pretreated Jurkat cells with methyl-β-cyclodextrin (MβCD), a cholesterol depleting agent that disrupts the integrity of lipid rafts.…”

Section: Resultsmentioning

confidence: 99%

Exogenous Hydrogen Peroxide Induces Lipid Raft-Mediated STAT-6 Activation in T Cells

Kim¹,

Lim²,

Jang³

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: CD4+ T cells are a critical component of the adaptive immune response. While the mechanisms controlling the differentiation of the Th1, Th17, and regulatory T cell subsets from naïve CD4+ T cells are well described, the factors that induce Th2 differentiation are still largely unknown. Methods: The effects of treatment with exogenous H₂O₂ on STAT-6 phosphorylation and activation in T cells were examined by immunoblotting, immunofluorescence and gel shift assay. Anti-CD3 antibody and methyl-β-cyclodextrin were utilized to induce lipid raft assembly and to investigate the involvement of lipid rafts, respectively. Results: Jurkat and EL-4 T cells that were exposed to H₂O₂ showed rapid and strong STAT-6 phosphorylation, and the extent of STAT-6 phosphorylation was enhanced by co-treatment with anti-CD3 antibody. The effect of H₂O₂ on STAT-6 phosphorylation and translocation was inhibited by disruption of lipid rafts. STAT-6 activation in response to H₂O₂ treatment regulated IL-4 gene expression, and this response was strengthened by treatment with anti-CD3. Conclusion: Our results indicate that reactive oxygen species such as H₂O₂ can act on upstream and initiating factors for activation of STAT-6 in T cells and contribute to formation of a positive feedback loop between STAT-6 and IL-4 in the Th2 differentiation process.

show abstract

“…Previous studies demonstrated that hydrogen peroxide (H 2 O 2 ) and hypoxia (CoCl 2 ) induce apoptosis in cultured primary astrocytes [32][33][34]. Whether leptin has anti-apoptotic and necrotic effect on oxidative stress-induced apoptosis was evaluated using Annexin V-FITC/PI double staining monitored by flow cytometry.…”

Section: Leptin Has a Protective Effect Against Glutamate-induced Apomentioning

confidence: 99%

Leptin Suppresses Glutamate-Induced Apoptosis Through Regulation of ERK1/2 Signaling Pathways in Rat Primary Astrocytes

Park

Ahn

Jung

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Leptin is a hormone expressed by adipose tissue that regulates body energy homeostasis and weight loss by activating leptin receptors in the hypothalamus. Leptin receptors are also expressed in astrocytes. An anti-apoptosis effect of leptin in brain has recently been reported. However, the anti-apoptosis mechanism of leptin in the brain is unknown. Methods: To investigate whether leptin exerts protective effects against glutamateinduced apoptosis in astrocytes, we performed cell viability assays and apoptosis assays using rat primary astrocytes. Intracellular signaling pathways involved in anti-apoptosis effects of leptin were analyzed by immunoblotting together with a leptin mutant (S120A/T121A) with antagonist function and pharmacological inhibitors. Results: We found that glutamateinduced apoptosis in rat primary astrocytes was significantly decreased by treatment with leptin. Leptin inhibited glutamate-induced phosphorylation of ERK1/2 in astrocytes. The leptin S120A/T121A mutant did not inhibit glutamate-induced ERK1/2 phosphorylation and ERK1/2-mediated apoptosis. Conclusions: Collectively, our results provide initial evidence that leptin exerts an anti-apoptotic effect against glutamate toxicity through activation of intracellular signaling pathways which reverse glutamate-induced ERK1/2 phosphorylation in primary astrocytes. Therefore, our findings suggest that leptin might be considered a candidate for potential therapeutic applications in glutamate-induced brain excitotoxicity.

show abstract

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Cited by 38 publications

References 63 publications

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

Exogenous Hydrogen Peroxide Induces Lipid Raft-Mediated STAT-6 Activation in T Cells

Leptin Suppresses Glutamate-Induced Apoptosis Through Regulation of ERK1/2 Signaling Pathways in Rat Primary Astrocytes

Contact Info

Product

Resources

About