Regulation of human IP-10 gene expression in astrocytoma cells by inflammatory cytokines

Majumder, Sarmila; Zhou, Lucy Z.-H.; Chaturvedi, Priya; Babcock, Gerald T.; Aras, Sümer; Ransohoff, Richard M.

doi:10.1002/(sici)1097-4547(19981015)54:2<169::aid-jnr5>3.0.co;2-c

Cited by 71 publications

(47 citation statements)

References 27 publications

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“…The promoter regions for both of these chemokines contain several transcription regulatory elements, but analysis of the IL-8 promoter has shown that expression requires the activity of a combination of either NF-B and AP-1 or NF-B and NF-IL-6 (Mahe et al, 1991;Yasumoto et al, 1992). Maximal IP-10 expression also requires cooperation between two sites, with strong promoter activity involving both an interferon-stimulated response element and an NF-B site that binds a p65 homodimer (Majumder et al, 1998). The fact that activation of astrocytes with nucleotides in the presence of IL-1␤ led to the differential regulation of IL-1␤-induced IL-8 and IP-10 expression was unexpected, and at the present time the mechanism for this remains unclear.…”

Section: Discussionmentioning

confidence: 80%

Extracellular Nucleotides Differentially Regulate Interleukin-1β Signaling in Primary Human Astrocytes: Implications for Inflammatory Gene Expression

John¹,

Simpson

Woodroofe

et al. 2001

J. Neurosci.

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The cytokine interleukin-1␤ (IL-1␤) is a potent activator of human astrocytes, inducing or modulating expression of multiple proinflammatory genes via activation of the transcription factors nuclear factor-B (NF-B) and activator protein-1 (AP-1). In this study, we examined whether IL-1␤ signaling is regulated in these cells by extracellular nucleotides that are released at high concentrations under inflammatory conditions and act as ligands for members of the P2 receptor family. Using reporter constructs and electromobility shift assays, we found that cotreatment of astrocyte cultures with ATP (1-100 M) significantly potentiated IL-1␤-mediated activation of NF-B and AP-1 and that ATP alone activated AP-1. These effects were blocked by the P2 receptor antagonists XAMR 0721, periodate-oxidized ATP, and suramin. A role for ATP in modulating IL-1␤-mediated inflammatory gene expression was supported further by the observation that ATP potentiated the IL-1␤-induced expression of IL-8 mRNA and protein but strongly downregulated IP-10 expression. Reverse transcription-PCR and cloning demonstrated expression of the ATP-responsive P2 receptor subtypes P2Y 1 , P2Y 2 , and P2X 7 , as well as the ATP-insensitive receptor P2Y 4 . ADP, a selective agonist for P2Y 1 , produced results similar to or greater than those obtained using ATP, whereas 2Ј-3Ј-O-(4-benzoylbenzoyl)-ATP, a selective agonist for P2X 7 , was less effective than ATP. In contrast, UTP, a selective agonist for P2Y 2 and P2Y 4 , was ineffective. These studies indicate that different P2 receptor subtypes play distinct roles in the modulation of IL-1␤-mediated signal transduction in human astrocytes, and that signaling via P2 receptors may fine-tune the transcription of genes involved in inflammatory responses in the human CNS.

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Section: Discussionmentioning

confidence: 80%

Extracellular Nucleotides Differentially Regulate Interleukin-1β Signaling in Primary Human Astrocytes: Implications for Inflammatory Gene Expression

John¹,

Simpson

Woodroofe

et al. 2001

J. Neurosci.

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“…IFNgmediated induction of IP-10 can be seen in most IP-10-expressing cell types including monocytes/macrophages, although in dermal fibroblasts and astrocytoma cells, the induction is weak and TNFa or a combination of IFNg/TNFa are required. 21,40 The physiological relevance of this regulation is not yet understood, as local IFNg concentrations in adipose tissue have not been investigated. Given the fact that potentially IFNg-producing T cells have been found in epicardial tissue, 33 paracrine effects of IFNg-secreting immune cells on adipocytes seem conceivable.…”

Section: Discussionmentioning

confidence: 99%

Constitutive and regulated expression and secretion of interferon-γ-inducible protein 10 (IP-10/CXCL10) in human adipocytes

et al. 2006

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“…For EMSAs, where indicated, the cells were stimulated with IL-1␤ or TNF for 20 min. The NF-B binding site (5Ј-GAGCAGAGGGAAATTCCGTA-ACTT-3Ј) from the IFN-inducible protein 10 (IP-10) gene was used as a probe (44). Complementary oligonucleotides, endlabeled with polynucleotide kinase and ␥-32 P-labeled ATP, were annealed by slow cooling.…”

Section: Cell Line For Mutagenesis and Generation Of Constitutive Mutmentioning

confidence: 99%

Mutant human cells with constitutive activation of NF-κB

Sathe

Sizemore

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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We have used a genetic approach to generate eight different mutant human cell lines in which NF-B is constitutively activated. These independent clones have different phenotypes and belong to several different genetic complementation groups. In one clone inhibitor of B (I B) kinase is constitutively active, but in the seven others it is not, despite the fact that I B is degraded in all eight clones. Thus, I B kinase-independent mechanisms of I B degradation and NF-B activation are predominant in these mutants. Biochemical analyses of the mutants revealed that they fall into at least five different categories, differing in the sets of upstream kinases that are activated, confirming multiple mechanisms of NF-B activation. By introducing a retroviral cDNA library into the Ras C6 cell line, with constitutively active NF-B, followed by selection for functional complementation, we isolated a cDNA encoding a C-terminal fragment of enolase 1 and identified it as negative regulator of NF-B.forward genetics ͉ complementation groups ͉ functional complementation ͉ enolase 1 ͉ ras

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Regulation of human IP-10 gene expression in astrocytoma cells by inflammatory cytokines

Cited by 71 publications

References 27 publications

Extracellular Nucleotides Differentially Regulate Interleukin-1β Signaling in Primary Human Astrocytes: Implications for Inflammatory Gene Expression

Extracellular Nucleotides Differentially Regulate Interleukin-1β Signaling in Primary Human Astrocytes: Implications for Inflammatory Gene Expression

Constitutive and regulated expression and secretion of interferon-γ-inducible protein 10 (IP-10/CXCL10) in human adipocytes

Mutant human cells with constitutive activation of NF-κB

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