Molecular mechanisms underlying the inhibition of IFN‐γ‐induced, STAT1‐mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs

Li, Na; Salter, Rebecca Claire; Ramji, Dipak Purshottam

doi:10.1002/jcb.22976

Cited by 24 publications

(15 citation statements)

References 33 publications

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“…CXCL10 expression is regulated by STAT1 in response to LPS [26] and LXR activation has previously been shown to reduce STAT1 phosphorylation in the human macrophage THP-1 cell line [27]. We therefore studied the effect of GW3965 on STAT1 phosphorylation in LPS stimulated macrophages from 3 S and 3 COPD patients.…”

Section: Resultsmentioning

confidence: 99%

The role of the liver X receptor in chronic obstructive pulmonary disease

Higham¹,

Lea²,

Plumb³

et al. 2013

Respir Res

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BackgroundThere is a need for novel anti-inflammatory therapies to treat COPD. The liver X receptor (LXR) is a nuclear hormone receptor with anti-inflammatory properties.MethodsWe investigated LXR gene and protein expression levels in alveolar macrophages and whole lung tissue from COPD patients and controls, the effect of LXR activation on the suppression of inflammatory mediators from LPS stimulated COPD alveolar macrophages, and the effect of LXR activation on the induction of genes associated with alternative macrophage polarisation.ResultsThe levels of LXR mRNA were significantly increased in whole lung tissue extracts in COPD patients and smokers compared to non-smokers. The expression of LXR protein was significantly increased in small airway epithelium and alveolar epithelium in COPD patients compared to controls. No differences in LXR mRNA and protein levels were observed in alveolar macrophages between patient groups. The LXR agonist GW3965 significantly induced the expression of the LXR dependent genes ABCA1 and ABCG1 in alveolar macrophage cultures. In LPS stimulated alveolar macrophages, GW3965 suppressed the production of CXCL10 and CCL5, whilst stimulating IL-10 production.ConclusionsGW3965 did not significantly suppress the production of TNFα, IL-1β, or CXCL8. Our major finding is that LXR activation has anti-inflammatory effects on CXC10, CCL5 and IL-10 production from alveolar macrophages.

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Section: Resultsmentioning

confidence: 99%

The role of the liver X receptor in chronic obstructive pulmonary disease

Higham¹,

Lea²,

Plumb³

et al. 2013

Respir Res

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“…SUMOylated LXRs formed a complex with STAT1 in astrocytes resulting in inhibited recruitment of STAT1 to the interferon-regulatory factor (IRF)-1 promoter, without affecting STAT1 phosphorylation or its nuclear translocation ). An independent report, however, did observe reduced levels of IFN-c-induced STAT1 serine and tyrosine phosphorylation in human THP-1 macrophages in response to 22 (R)-hydroxycholesterol (Li et al 2011).…”

Section: Lxrs As Negative Regulators Of Inflammationmentioning

confidence: 87%

Biological Roles of Liver X Receptors in Immune Cells

Pascual-García

Valledor

2012

Arch. Immunol. Ther. Exp.

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Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are activated by specific oxysterols. LXRs heterodimerize with retinoid X receptors to regulate positively the expression of a variety of target genes, many of which are involved in lipid and glucose metabolism. In the last few years, new targets of LXR activation have been identified with roles in the modulation of immune responses. Moreover, LXRs mediate repression of inflammatory pathways through mechanisms collectively known as transrepression. Here, we revise recent findings on the impact of LXR activation on immune responses, with an emphasis on advances in the understanding of the molecular mechanisms that mediate these effects.

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“…LXRs regulate inflammation by inhibiting the expression of inflammatory mediators including interleukin-6, nitric oxide synthase and cyclooxygenase 2 (Bensinger et al, 2008;Joseph et al, 2003). Mechanistically, the antiinflammatory effects of LXRs have been attributed to the inhibition of nuclear factor kappa-B and STAT1-mediated signaling pathways via transrepression (Glass and Saijo, 2010;Li et al, 2011). LXRA-deficient mice have been shown to be more susceptible to bacterial infection due to accelerated macrophage apoptosis and a reduced immune response (Joseph et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Wang¹,

Sadovnick²,

Traboulsee³

et al. 2016

Neuron

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SUMMARYMultiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

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Molecular mechanisms underlying the inhibition of IFN‐γ‐induced, STAT1‐mediated gene transcription in human macrophages by simvastatin and agonists of PPARs and LXRs

Cited by 24 publications

References 33 publications

The role of the liver X receptor in chronic obstructive pulmonary disease

The role of the liver X receptor in chronic obstructive pulmonary disease

Biological Roles of Liver X Receptors in Immune Cells

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

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