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PMID:21268089

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Citation

Li, N, Salter, RC and Ramji, DP (2011) Molecular mechanisms underlying the inhibition of IFN-γ-induced, STAT1-mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs. J. Cell. Biochem. 112:675-83

Abstract

PPARs and LXRs are ligand-activated transcription factors that are emerging as promising therapeutic targets for limiting atherosclerosis, an inflammatory disorder orchestrated by cytokines. The potent anti-atherogenic actions of these nuclear receptors involve the regulation of glucose and lipid metabolism along with attenuation of the inflammatory response. Similarly, cholesterol-lowering drugs, statins, inhibit inflammation. Unfortunately, the mechanisms underlying such inhibitory actions of these agents in human macrophages are poorly understood and were therefore investigated in relation to IFN-γ, a key pro-atherogenic cytokine, which mediates its cellular effects mainly through STAT1. Simvastatin and PPAR agonists had no effect on the IFN-γ-induced, phosphorylation-mediated activation of STAT1 and its DNA binding but attenuated its ability to activate gene transcription. On the other hand, LXR activators attenuated both DNA binding and trans-activation potential of STAT1 induced by IFN-γ. These studies reveal differences in the mechanism of action of agonists of PPARs (and simvastatin) and LXRs on the IFN-γ-induced, STAT1-mediated gene transcription in human macrophages.

Links

PubMed Online version:10.1002/jcb.22976

Keywords

Blotting, Western; Butyric Acids/pharmacology; Cell Line; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Electrophoretic Mobility Shift Assay; Humans; Hydrocarbons, Fluorinated/pharmacology; Interferon-gamma/pharmacology; Macrophages/drug effects; Macrophages/metabolism; Orphan Nuclear Receptors/agonists; Orphan Nuclear Receptors/metabolism; Peroxisome Proliferator-Activated Receptors/agonists; Peroxisome Proliferator-Activated Receptors/metabolism; Phenylurea Compounds/pharmacology; STAT1 Transcription Factor/metabolism; Simvastatin/pharmacology; Sulfonamides/pharmacology; Thiazolidinediones/pharmacology; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:STAT1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:STAT1

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0000167)

Seeded From UniProt

complete

HUMAN:STAT1

enables

GO:0000981: DNA-binding transcription factor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:STAT1

involved_in

GO:0060333: interferon-gamma-mediated signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H2

involved_in

GO:0060336: negative regulation of interferon-gamma-mediated signaling pathway

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR1H3

involved_in

GO:0060336: negative regulation of interferon-gamma-mediated signaling pathway

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IFNG

involved_in

GO:0033141: positive regulation of peptidyl-serine phosphorylation of STAT protein

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PPARG

involved_in

GO:0060336: negative regulation of interferon-gamma-mediated signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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