FHL2 Protein Is a Novel Co-repressor of Nuclear Receptor Nur77

Kurakula, Kondababu; Wal, Erik van der; Geerts, Dirk; Tiel, Claudia M. van; Vries, Carlie J.M. de

doi:10.1074/jbc.m111.308999

Cited by 41 publications

(63 citation statements)

References 46 publications

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“…For luciferase assay, cells were transfected with an NF-kB reporter plasmid using Lipofectamine LTX plus transfection reagent (Life Technologies) according to the manufacturer's protocol, and assay was described previously (31). The construct containing the NF-kB response element of the minimal IL-6 promoter was provided by Dr. Karolien De Bosscher (Ghent University, Ghent, Belgium) and described previously (33).…”

Section: Cell Culture and Lentiviral Transductionmentioning

confidence: 99%

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Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Kurakula

Vos

Logiantara

et al. 2015

The Journal of Immunology

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Allergic asthma is characterized by persistent chronic airway inflammation, which leads to mucus hypersecretion and airway hyperresponsiveness. Nuclear receptor Nur77 plays a pivotal role in distinct immune and inflammatory cells and is expressed in eosinophils and lung epithelium. However, the role of Nur77 in allergic airway inflammation has not been studied so far. In the present study, we determined the role of Nur77 in airway inflammation using a murine model of OVA-induced allergic airway inflammation. We found that OVA-challenged Nur77 knockout (KO) mice show significantly enhanced infiltration of inflammatory cells, including eosinophils and lymphocytes, and aggravated mucus production. The infiltration of macrophages is limited in this model and was similar in wild-type and Nur77 KO mice. Higher levels of Th2 cytokines were found in bronchoalveolar lavage fluid and draining lymph node cells of Nur77-KO mice, as well as increased serum IgG1 and IgG2a levels. Knockdown of Nur77 in human lung epithelial cells resulted in a marked increase in IκBα phosphorylation, corresponding with elevated NF-κB activity, whereas Nur77 overexpression decreased NF-κB activity. Consistently, Nur77 significantly decreased mRNA levels of inflammatory cytokines and Muc5ac expression and also attenuated mucus production in lung epithelial cells. To further corroborate these findings, we searched for association of single nucleotide polymorphisms in Nur77 gene with asthma and with the severity of bronchial hyperresponsiveness. We identified three Nur77 single nucleotide polymorphisms showing association with severity of bronchial hyperresponsiveness in asthma patients. Collectively, these findings support a protective role of Nur77 in OVA-induced airway inflammation and identify Nur77 as a novel therapeutic target for airway inflammation.

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Section: Cell Culture and Lentiviral Transductionmentioning

confidence: 99%

“…Recombinant lentiviral particles encoding Nur77 and short hairpin RNA targeting Nur77 were produced, concentrated, and titrated as described previously (31). The human short hairpin RNA oligonucleotide sequences of Nur77 were described earlier (20).…”

Section: Cell Culture and Lentiviral Transductionmentioning

confidence: 99%

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Kurakula

Vos

Logiantara

et al. 2015

The Journal of Immunology

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“…FHL2, also known as DRAL or SLIM3, is the second member of the four-and-a-half-LIM-domain protein family (8,9), which possesses an amino-terminal half LIM domain followed by four complete LIM domains. LIM proteins mediate protein-protein interactions and sometimes bind DNA or mediate nuclear localization (10,11).…”

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confidence: 99%

LIM-Only Protein FHL2 Is a Positive Regulator of Liver X Receptors in Smooth Muscle Cells Involved in Lipid Homeostasis

Kurakula

Sommer

Sokolović

et al. 2015

Molecular and Cellular Biology

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bThe LIM-only protein FHL2 is expressed in smooth muscle cells (SMCs) and inhibits SMC-rich-lesion formation. To further elucidate the role of FHL2 in SMCs, we compared the transcriptomes of SMCs derived from wild-type (WT) and FHL2 knockout (KO) mice. This revealed that in addition to the previously recognized involvement of FHL2 in SMC proliferation, the cholesterol synthesis and liver X receptor (LXR) pathways are altered in the absence of FHL2. Using coimmunoprecipitation experiments, we found that FHL2 interacts with the two LXR isoforms, LXR␣ and LXR␤. Furthermore, FHL2 strongly enhances transcriptional activity of LXR element (LXRE)-containing reporter constructs. Chromatin immunoprecipitation (ChIP) experiments on the ABCG1 promoter revealed that FHL2 enhances the association of LXR␤ with DNA. In line with these observations, we observed reduced basal transcriptional LXR activity in FHL2-KO SMCs compared to WT SMCs. This was also reflected in reduced expression of LXR target genes in intact aorta and aortic SMCs of FHL2-KO mice. Functionally, the absence of FHL2 resulted in attenuated cholesterol efflux to both ApoA-1 and high-density lipoprotein (HDL), in agreement with reduced LXR signaling. Collectively, our findings demonstrate that FHL2 is a transcriptional coactivator of LXRs and points toward FHL2 being an important determinant of cholesterol metabolism in SMCs.

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“…37 Conversely, Nur77 overexpression reduces inflammatory cytokine synthesis in macrophages. 38 Because FHL2 can bind to Nur77 and repress its function, 39 enhanced Nur77 activity in ApoE/FHL2 −/− mice could account, at least in part, for the preferential recruitment of patrolling monocytes and reduced atherosclerotic lesion formation in these animals.…”

Section: Discussionmentioning

confidence: 99%

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE ^−/− Mice

Ebrahimian

Simon

Lemarié

et al. 2015

ATVB

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A therosclerosis is a chronic inflammatory disease that is characterized by modifications in the vascular, metabolic, and immune systems. The accumulation of leukocytes within atherosclerotic lesions is a process regulated at various levels, including mobilization, recruitment, and endothelial adhesion of monocytes, followed by their migration into the intima and differentiation into macrophages.1,2 Two major monocyte subsets can be distinguished in the blood based on differential expression of the chemokine receptors CCR2 and CX 3 CR1. The inflammatory monocytes express high levels of CCR2 but low levels of CX 3 CR1, whereas the patrolling monocytes have low levels of CCR2 and high levels of CX 3 CR1.3,4 Inflammatory monocytes rapidly enter the atherosclerotic plaque where they give rise to macrophages. As macrophages accumulate in the atherosclerotic lesion, they incorporate lipids and become foam cells, eventually forming necrotic cores that fragilize the plaque. The inflammatory milieu attracts diverse immune cells but also promotes vascular smooth muscle cell (VSMC) infiltration from the media. Accumulation of VSMCs and collagen synthesis by these cells is associated with a reduced risk of rupture. 5Four-and-a-half LIM domain protein 2 (FHL2, SLIM3) is the best-studied member of the LIM-only subclass of the LIM protein superfamily. LIM proteins are defined by the presence of ≥1 LIM domains composed of a conserved cysteine-rich module that mediates protein-protein interactions. 6 Multiple roles have been ascribed to FHL2. FHL2 exerts its function as a transcriptional cofactor, interacting with a broad range of transcription factors, and modulating the transcription of many proteins such as the androgen receptor, cAMP response element-binding protein, integrins, β-catenin, presenilin-2, ERK-2 (extracellular signal-regulated kinase), AP-1, and sphingosine kinase-1. [7][8][9][10][11][12] It modulates cellular processes such as cell survival, proliferation, and signal transduction.13 FHL2© 2015 American Heart Association, Inc.

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FHL2 Protein Is a Novel Co-repressor of Nuclear Receptor Nur77

Cited by 41 publications

References 46 publications

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

LIM-Only Protein FHL2 Is a Positive Regulator of Liver X Receptors in Smooth Muscle Cells Involved in Lipid Homeostasis

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE ^−/− Mice

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FHL2 Protein Is a Novel Co-repressor of Nuclear Receptor Nur77

Cited by 41 publications

References 46 publications

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-κB Activity in Lung Epithelial Cells

LIM-Only Protein FHL2 Is a Positive Regulator of Liver X Receptors in Smooth Muscle Cells Involved in Lipid Homeostasis

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE −/− Mice

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Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE ^−/− Mice