A role for IRF3-dependent RXRα repression in hepatotoxicity associated with viral infections

Chow, Edward K.; Castrillo, Antonio; Shahangian, Arash; Pei, Liming; O’Connell, Ryan M.; Modlin, Robert L.; Tontonoz, Peter; Cheng, Genhong

doi:10.1084/jem.20060929

Cited by 37 publications

(36 citation statements)

References 72 publications

(107 reference statements)

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“…Although the mechanisms of type I IFN induction by IRF-3 are well established, IFNindependent IRF-3 activation is not fully understood. Recent studies suggest that IRF-3 directly induces the transcriptional suppresser Hes1 independently of IFN-␤, which in turn inhibits the expression of the nuclear receptor RXRA (55). Inhibition of RXRA by the activation of IRF-3 can reduce the expression of RXRA target genes including the metabolic enzymes CYP3A4 and UGT1A6 (55).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggest that IRF-3 directly induces the transcriptional suppresser Hes1 independently of IFN-␤, which in turn inhibits the expression of the nuclear receptor RXRA (55). Inhibition of RXRA by the activation of IRF-3 can reduce the expression of RXRA target genes including the metabolic enzymes CYP3A4 and UGT1A6 (55). The studies of Li et al (56) indicate that keratinocyte-selective ablation of RXRA and retinoid X receptor ␤ induces TSLP expression in epidermal keratinocytes, which results in an atopic dermatitis-like syndrome.…”

Section: Discussionmentioning

confidence: 99%

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TLR3- and Th2 Cytokine-Dependent Production of Thymic Stromal Lymphopoietin in Human Airway Epithelial Cells

Kato

Favoreto

Avila

et al. 2007

The Journal of Immunology

440

428

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Thymic stromal lymphopoietin (TSLP) is elevated in asthma and triggers dendritic cell-mediated activation of Th2 inflammatory responses. Although TSLP has been shown to be produced mainly by airway epithelial cells, the regulation of epithelial TSLP expression has not been extensively studied. We investigated the expression of TSLP in cytokine- or TLR ligand-treated normal human bronchial epithelial cells (NHBE). The mRNA for TSLP was significantly up-regulated by stimulation with IL-4 (5.5-fold) and IL-13 (5.3-fold), weakly up-regulated by TNF-α, TGF-β, and IFN-β, and not affected by IFN-γ in NHBE. TSLP mRNA was only significantly up-regulated by the TLR3 ligand (dsRNA) among the TLR ligands tested (66.8-fold). TSLP was also induced by in vitro infection with rhinovirus. TSLP protein was detected after stimulation with dsRNA (120 ± 23 pg/ml). The combination of TNF-α and IL-4 produced detectable levels of TSLP protein (40 ± 13 pg/ml). In addition, TSLP was synergistically enhanced by a combination of IL-4 and dsRNA (mRNA; 207-fold, protein; 325 ± 75 pg/ml). The induction of TSLP by dsRNA was dependent upon NF-κB and IFN regulatory factor 3 (IRF-3) signaling via TLR3 as indicated by a study with small interfering RNA. The potent topical glucocorticoid fluticasone propionate significantly suppressed dsRNA-dependent TSLP production in NHBE. These results suggest that the expression of TSLP is induced in airway epithelial cells by stimulation with the TLR3 ligand and Th2 cytokines and that this response is suppressed by glucocorticoid treatment. This implies that respiratory viral infection and the recruitment of Th2 cytokine producing cells may amplify Th2 inflammation via the induction of TSLP in the asthmatic airway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TLR3- and Th2 Cytokine-Dependent Production of Thymic Stromal Lymphopoietin in Human Airway Epithelial Cells

Kato

Favoreto

Avila

et al. 2007

The Journal of Immunology

440

428

View full text Add to dashboard Cite

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“…This nuclear receptor is active as a heterodimer with retinoid X receptor (RXR). Repression of PPARG activity could involve suppression of RXR␣-dependent gene expression due to Jun N-terminal protein kinase (JNK) phosphorylation, itself activated by tumor necrosis factor alpha (TNF-␣) and interleukin 1 (IL-1) signaling (57), or RXR␣ repression mediated by IRF3 in hepatocytes and BMMs (8). Known targets of PPARG that were DE between MA-CA/04 and CA/04 infection were associated with lipid metabolism and the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Josset

Belser

Pantin‐Jackwood

et al. 2012

J Virol

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“…Our previous work determined that IRF9 interacts with peroxisome proliferator-activated receptor (PPAR)-␣ to attenuate NAFLD (42). IRF3 was reported to regulate metabolism-related nuclear receptors, such as liver X receptor (LXR) and retinoid X receptor ␣ (4,8). Another group found that IRFs regulate adipogenesis and lipid metabolism in adipocytes (10,11).…”

mentioning

confidence: 99%

Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance

Wang

Zhang

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am J Physiol Endocrinol Metab 305: E485-E495, 2013. First published May 20, 2013 doi:10.1152/ajpendo.00505.2012.-Obesity-related inflammation has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. In this study, we addressed the potential role of interferon regulatory factor 7 (IRF7), a master regulator of type I interferon-dependent immune responses, in the regulation of energy metabolism. The expression levels of IRF7 were increased in white adipose tissue, liver tissue, and gastrocnemius muscle of both dietinduced obese mice and ob/ob mice compared with their lean counterparts. After feeding a high-fat diet (HFD) for 24 wk, IRF7 knockout (KO) mice showed less weight gain and adiposity than wild-type controls. KO of IRF7 improved glucose and lipid homeostasis and insulin sensitivity. Additionally, KO of IRF7 ameliorated diet-induced hepatic steatosis. Next, we assessed the inflammatory state of the IRF7 KO mice on the HFD. These mice showed less macrophage infiltration into multiple organs and were protected from local and systemic inflammation. This study demonstrates a role for IRF7 in diet-induced alterations in energy metabolism and insulin sensitivity. Our results also suggest that IRF7 is involved in the etiology of metabolic abnormalities, which suggests a new strategy for treating obesity and type 2 diabetes. type 2 diabetes; adiposity; fatty liver; inflammation UNDER NORMAL PHYSIOLOGICAL conditions, organisms have a finetuned regulatory network to maintain metabolic homeostasis. However, energy imbalance develops with caloric excess and compromised regulatory functions that accompany aging. This imbalance leads to obesity, nonalcoholic fatty liver diseases (NAFLD), metabolic syndrome, and type 2 diabetes, which pose great challenges to public health (5, 45a). Obesity is now recognized as a chronic low-grade inflammatory state (19). Inflammatory mediators and cytokines are overexpressed in the adipose and other tissues in the obese state (45). Infiltration of immune cells and proinflammatory M1 polarization of macrophages are also associated with obesity (24). Activation of inflammatory signaling pathways, including c-Jun NH 2 -terminal kinase (JNK)/activator protein 1 (AP1) and IKK/NF-B pathways, blunts insulin activity (13). Loss of IB kinase ε (IKKε, also known as IKKi), a target gene of NF-B, has also been reported to improve the energy balance in diet-induced obese mice (7, 33). In addition to systemic inflammation, ectopic lipid accumulation and endoplasmic reticulum (ER) stress were also proposed to explain the pathogenesis of insulin resistance (12, 34). However, the underlying mechanism of obesity-related metabolic disorders is still not completely understood.Interferon (IFN) ␣ and IFN␤, collectively known as type I IFNs, are the major mediators of the host immune response against viral infections (14, 31). IFN regulatory factors (IRF) are a family of transcription facto...

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A role for IRF3-dependent RXRα repression in hepatotoxicity associated with viral infections

Cited by 37 publications

References 72 publications

TLR3- and Th2 Cytokine-Dependent Production of Thymic Stromal Lymphopoietin in Human Airway Epithelial Cells

TLR3- and Th2 Cytokine-Dependent Production of Thymic Stromal Lymphopoietin in Human Airway Epithelial Cells

Implication of Inflammatory Macrophages, Nuclear Receptors, and Interferon Regulatory Factors in Increased Virulence of Pandemic 2009 H1N1 Influenza A Virus after Host Adaptation

Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance

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