Modulation of interferon‐γ‐induced glial cell activation by transforming growth factor β1: A role for STAT1 and MAPK pathways

Herrera-Molina, Rodrigo; Flores, Betsi; Orellana, Juan A.; Bernhardi, Rommy von

doi:10.1111/j.1471-4159.2012.07887.x

Cited by 29 publications

(30 citation statements)

References 59 publications

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“…Since IFNγ-induced ROS production was inhibited by the MEK inhibitor (U0126, Figure 12B), it is reasonable to conclude that p-ERK1/2 plays an important role in the induction process. Our results support earlier studies demonstrating the involvement of ERK1/2 from IFNγ to stimulate superoxide in a mixed glial cell culture [36]. Our study further provided evidence for involvement of NADPH oxidase in IFNγ-induced ROS production in microglial cells.…”

Section: Discussionsupporting

confidence: 92%

“…There is evidence that signaling molecules, such as protein kinase C and mitogen-activated protein kinase (MAPK), can mediate the cross-talk pathways [22,33]. In studies with microglial cells, increase in MAPK-ERK1/2 activity has been shown to occur during induction of iNOS by LPS and IFNγ [34-36]. Our results here also demonstrated the ability for IFNγ alone to stimulate phosphorylation of ERK1/2 in microglial cells (Figure 9A, B).…”

Section: Discussionmentioning

confidence: 99%

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Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells

Chuang

Chan

Zong

et al. 2013

J Neuroinflammation

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BackgroundThe bark of magnolia has been used in Oriental medicine to treat a variety of remedies, including some neurological disorders. Magnolol (Mag) and honokiol (Hon) are isomers of polyphenolic compounds from the bark of Magnolia officinalis, and have been identified as major active components exhibiting anti-oxidative, anti-inflammatory, and neuroprotective effects. In this study, we investigate the ability of these isomers to suppress oxidative stress in neurons stimulated by the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) and oxidative and inflammatory responses in microglial cells activated by interferon-γ (IFNγ) and lipopolysaccharide (LPS). We also attempt to elucidate the mechanism and signaling pathways involved in cytokine-induced production of reactive oxygen species (ROS) in microglial cells.MethodsDihydroethidium (DHE) was used to assay superoxide production in neurons, while CM-H2DCF-DA was used to test for ROS production in murine (BV-2) and rat (HAPI) immortalized microglial cells. NADPH oxidase inhibitors (for example, diphenyleneiodonium (DPI), AEBSF, and apocynin) and immunocytochemistry targeting p47phox and gp91phox were used to assess the involvement of NADPH oxidase. Western blotting was used to assess iNOS and ERK1/2 expression, and the Griess reaction protocol was employed to determine nitric oxide (NO) concentration.ResultsExposure of Hon and Mag (1–10 μM) to neurons for 24 h did not alter neuronal viability, but both compounds (10 μM) inhibited NMDA-stimulated superoxide production, a pathway known to involve NADPH oxidase. In microglial cells, Hon and Mag inhibited IFNγ±LPS-induced iNOS expression, NO, and ROS production. Studies with inhibitors and immunocytochemical assay further demonstrated the important role of IFNγ activating the NADPH oxidase through the p-ERK-dependent pathway. Hon and, to a lesser extent, Mag inhibited IFNγ-induced p-ERK1/2 and its downstream pathway for ROS and NO production.ConclusionThis study highlights the important role of NADPH oxidase in mediating oxidative stress in neurons and microglial cells and has unveiled the role of IFNγ in stimulating the MAPK/ERK1/2 signaling pathway for activation of NADPH oxidase in microglial cells. Hon and Mag offer anti-oxidative or anti-inflammatory effects, at least in part, through suppressing IFNγ-induced p-ERK1/2 and its downstream pathway.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells

Chuang

Chan

Zong

et al. 2013

J Neuroinflammation

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“…() and Herrera‐Molina et al . (), we also observed a significant reduction in STAT1 phosphorylation after TGFβ1 treatment. In addition to this mechanism, we further detected reduced levels of phosphorylated STAT2.…”

Section: Discussionsupporting

confidence: 74%

TGFβ1 inhibits IFNγ‐mediated microglia activation and protects mDA neurons from IFNγ‐driven neurotoxicity

Zhou

Zöller

Krieglstein

et al. 2015

Journal of Neurochemistry

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Microglia-mediated neuroinflammation has been reported as a common feature of familial and sporadic forms of Parkinson 0 s disease (PD), and a growing body of evidence indicates that onset and progression of PD correlates with the extent of neuroinflammatory responses involving Interferon c (IFNc). Transforming growth factor b1 (TGFb1) has been shown to be a major player in the regulation of microglia activation states and functions and, thus, might be a potential therapeutic agent by shaping microglial activation phenotypes during the course of neurodegenerative diseases such as PD. In this study, we demonstrate that TGFb1 is able to block IFNc-induced microglia activation by attenuating STAT1 phosphorylation and IFNcRa expression. Moreover, we identified a set of genes involved in microglial IFNc signaling transduction that were significantly down-regulated upon TGFb1 treatment, resulting in decreased sensitivity of microglia toward IFNc stimuli. Interestingly, genes mediating negative regulation of IFNc signaling, such as SOCS2 and SOCS6, were upregulated after TGFb1 treatment. Finally, we demonstrate that TGFb1 is capable of protecting midbrain dopaminergic (mDA) neurons from IFNc-driven neurotoxicity in mixed neuron-glia cultures derived from embryonic day 14 (E14) midbrain tissue. Together, these data underline the importance of TGFb1 as a key immunoregulatory factor for microglia by silencing IFNcmediated microglia activation and, thereby, rescuing mDA neurons from IFNc-induced neurotoxicity.

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“…Studies from our laboratory have shown that the activity of microglia in vitro is modulated by TGFβ1, which is produced mainly by astrocytes, decreasing NO and ROS production induced by LPS and IFNγ (Herrera-Molina & von Bernhardi, 2005; Herrera-Molina et al 2012) and reducing neurotoxicity (Ramírez et al 2005). However, it is known that TGFβ1 can have both beneficial and deleterious effects on various diseases (Lesne et al 2003; Wyss-Coray et al 1997; 2001).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent changes on TGFβ1 Smad3 pathway modify the pattern of microglial cell activation

Tichauer

Flores

Soler

et al. 2014

Brain, Behavior, and Immunity

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Summary Aging is the main risk factor for Alzheimer's disease. Among other characteristics, it shows changes in inflammatory signaling that could affect the regulation of glial cell activation. We have shown that astrocytes prevent microglial cell cytotoxicity by mechanisms mediated by TGFβ1. However, whereas TGFβ1 is increased, glial cell activation persists in aging. To understand this apparent contradiction, we studied TGFβ1-Smad3 signaling during aging and their effect on microglial cell function. TGFβ1 induction and activation of Smad3 signaling in the hippocampus by inflammatory stimulation was greatly reduced in adult mice. We evaluated the effect of TGFβ1-Smad3 pathway on the regulation of nitric oxide (NO) and reactive oxygen species (ROS) secretion, and phagocytosis of microglia from mice at different ages with and without in vivo treatment with lipopolysaccharide (LPS) to induce an inflammatory status. NO secretion was only induced on microglia from young mice exposed to LPS, and was potentiated by inflammatory preconditioning, whereas in adult mice the induction of ROS was predominant. TGFβ1 modulated induction of NO and ROS production in young and adult microglia, respectively. Modulation was partially dependent on Smad3 pathway and was impaired by inflammatory preconditioning. Phagocytosis was induced by inflammation and TGFβ1 only in microglia cultures from young mice. Induction by TGFβ1 was also prevented by Smad3 inhibition. Our findings suggest that activation of the TGFβ1-Smad3 pathway is impaired in aging. Age-related impairment of TGFβ1-Smad3 can reduce protective activation while facilitating cytotoxic activation of microglia, potentiating microglia-mediated neurodegeneration.

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Modulation of interferon‐γ‐induced glial cell activation by transforming growth factor β1: A role for STAT1 and MAPK pathways

Cited by 29 publications

References 59 publications

Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells

Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells

TGFβ1 inhibits IFNγ‐mediated microglia activation and protects mDA neurons from IFNγ‐driven neurotoxicity

Age-dependent changes on TGFβ1 Smad3 pathway modify the pattern of microglial cell activation

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