Transcriptional response of human microglial cells to interferon-γ

Rock, R. Bryan; Hu, S; Deshpande, Ashlesha; Munir, Shirin; May, Barbara; Baker, Cristina A.; Peterson, Phillip K.; Kapur, Vivek

doi:10.1038/sj.gene.6364246

Cited by 96 publications

(71 citation statements)

References 48 publications

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“…1A) and protein (Fig. 3) levels appears to contradict the previous reports of an up-regulating effect of IFN-␥ on IL-33 mRNA in skin keratinocytes (32,33), cardiac myocytes, and fibroblasts (47), yet it is consistent with the previously observed apparent attenuating effect of IFN-␥ on IL-33 mRNA in macrophages and microglial cells (48,49). To clarify the Th1 and Th2 regulation of the IL-33 protein expression in the complexity of a realistic in vivo environment, AdV-mediated gene delivery was utilized (Fig.…”

Section: Effect Of Proteasome Lmp2 Subunit Inhibition On Ifn-␥-drivencontrasting

confidence: 56%

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IFN-γ Directly Controls IL-33 Protein Level through a STAT1- and LMP2-dependent Mechanism

Kopach

Lockatell

Pickering

et al. 2014

Journal of Biological Chemistry

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Background: IL-33 levels are regulated through poorly understood cytokine-dependent mechanisms. Results: IFN-␥ but not IL-4 down-regulates IL-33 protein by activating STAT1 and LMP2 proteasome, without engaging caspase-1, -3, or -8. Conclusion: Down-regulation of IL-33 protein by IFN-␥ requires STAT1 and non-canonical involvement of LMP2 proteasome. Significance: Understanding the mechanisms of IL-33 regulation is important for the development of IL-33-targeting therapies.

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Section: Effect Of Proteasome Lmp2 Subunit Inhibition On Ifn-␥-drivencontrasting

confidence: 56%

“…Some evidence suggests an IFN-␥-driven increase in IL-33 mRNA transcription in human skin keratinocytes (32,33), cardiac myocytes, and fibroblasts (47) but not dermal fibroblasts (32,33). By contrast, IFN-␥ appears to attenuate IL-33 mRNA expression in macrophages (48) and microglial cells (49).…”

mentioning

confidence: 99%

IFN-γ Directly Controls IL-33 Protein Level through a STAT1- and LMP2-dependent Mechanism

Kopach

Lockatell

Pickering

et al. 2014

Journal of Biological Chemistry

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“…The detection of CXCL12 in the cerebrospinal fluid of patients without neuroinflammatory diseases indicates that this chemokine does not necessarily promote inflammation within the CNS (28). Indeed, our data would argue that CXCL12 prevents CXCR4-expressing mononuclear cells from penetrating the CNS parenchyma, where they would contribute to microglial activation and demyelination via the actions of inflammatory mediators such as IFN-␥ (59,60). Consistent with this argument, Stumm et al (23) previously reported that the administration of LPS is associated with decreased expression of CXCL12 by CNS endothelial cells, supporting the notion that CXCL12 does not promote activation of the CNS microvasculature.…”

Section: Discussionmentioning

confidence: 94%

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

McCandless¹,

Wang

Woerner

et al. 2006

The Journal of Immunology

229

262

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The inflammatory response in the CNS begins with the movement of leukocytes across the blood-brain barrier in a multistep process that requires cells to pass through a perivascular space before entering the parenchyma. The molecular mechanisms that orchestrate this movement are not known. The chemokine CXCL12 is highly expressed throughout the CNS by microendothelial cells under normal conditions, suggesting it might play a role maintaining the blood-brain barrier. We tested this hypothesis in the setting of experimental autoimmune encephalomyelitis (EAE) by using AMD3100, a specific antagonist of the CXCL12 receptor CXCR4. We demonstrate that the loss of CXCR4 activation enhances the migration of infiltrating leukocytes into the CNS parenchyma. CXCL12 is expressed at the basolateral surface of CNS endothelial cells in normal spinal cord and at the onset of EAE. This polarity is lost in vessels associated with an extensive parenchymal invasion of mononuclear cells during the peak of disease. Inhibition of CXCR4 activation during the induction of EAE leads to loss of the typical intense perivascular cuffs, which are replaced with widespread white matter infiltration of mononuclear cells, worsening the clinical severity of the disease and increasing inflammation. Taken together, these data suggest a novel anti-inflammatory role for CXCL12 during EAE in that it functions to localize CXCR4-expressing mononuclear cells to the perivascular space, thereby limiting the parenchymal infiltration of autoreactive effector cells.

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“…In microglial cells, IFN-␥ induces changes in the expression level of at least 450 genes encoding chemokines, signaling molecules, and the MHC (17). IFN-␥ also increases microglial responses to A␤ peptides by the production of proinflammatory and neurotoxic mediators (18).…”

Section: A Lzheimer's Disease (Ad)mentioning

confidence: 99%

Induction of the Formyl Peptide Receptor 2 in Microglia by IFN-γ and Synergy with CD40 Ligand

Chen

Iribarren

Huang

et al. 2007

The Journal of Immunology

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Human formyl peptide receptor (FPR)-like 1 (FPRL1) and its mouse homologue mFPR2 are functional receptors for a variety of exogenous and host-derived chemotactic peptides, including amyloid β 1–42 (Aβ42), a pathogenic factor in Alzheimer’s disease. Because mFPR2 in microglial cells is regulated by proinflammatory stimulants including TLR agonists, in this study we investigated the capacity of IFN-γ and the CD40 ligand (CD40L) to affect the expression and function of mFPR2. We found that IFN-γ, when used alone, induced mFPR2 mRNA expression in a mouse microglial cell line and primary microglial cells in association with increased cell migration in response to mFPR2 agonists, including Aβ42. IFN-γ also increased the endocytosis of Aβ42 by microglial cells via mFPR2. The effect of IFN-γ on mFPR2 expression in microglial cells was dependent on activation of MAPK and IκB-α. IFN-γ additionally increased the expression of CD40 by microglial cells and soluble CD40L significantly promoted cell responses to IFN-γ during a 6-h incubation period by enhancing the activation of MAPK and IκB-α signaling pathways. We additionally found that the effect of IFN-γ and its synergy with CD40L on mFPR2 expression in microglia was mediated in part by TNF-α. Our results suggest that IFN-γ and CD40L, two host-derived factors with increased concentrations in inflammatory central nervous system diseases, may profoundly affect microglial cell responses in the pathogenic process in which mFPR2 agonist peptides are elevated.

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Transcriptional response of human microglial cells to interferon-γ

Cited by 96 publications

References 48 publications

IFN-γ Directly Controls IL-33 Protein Level through a STAT1- and LMP2-dependent Mechanism

IFN-γ Directly Controls IL-33 Protein Level through a STAT1- and LMP2-dependent Mechanism

CXCL12 Limits Inflammation by Localizing Mononuclear Infiltrates to the Perivascular Space during Experimental Autoimmune Encephalomyelitis

Induction of the Formyl Peptide Receptor 2 in Microglia by IFN-γ and Synergy with CD40 Ligand

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