PPARγ1 attenuates cytosol to membrane translocation of PKCα to desensitize monocytes/macrophages

Recently, we provided evidence that PKCα depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator–activated receptor γ (PPARγ) agonists dose dependently block PKCα depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte–derived macrophages. In these cells, we observed PPARγ-dependent inhibition of nuclear factor-κB (NF-κB) activation and TNF-α expression in response to PMA. Elucidating the underlying mechanism, we found PPARγ1 expression not only in the nucleus but also in the cytoplasm. Activation of PPARγ1 wild type, but not an agonist-binding mutant of PPARγ1, attenuated PMA-mediated PKCα cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein–protein interaction of PKCα and PPARγ1, which was further substantiated using a mammalian two-hybrid system. Applying PPARγ1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPARγ1 that is responsible for PKCα binding. Therefore, we conclude that PPARγ1-dependent inhibition of PKCα translocation implies a new model of macrophage desensitization.

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Gabapentin Reduces Alcohol Intake in Rats by Regulating NF-κB Signaling Pathway Via PPAR γ

Alcohol and Alcoholism ◽

10.1093/alcalc/agab065 ◽

2021 ◽

Author(s):

Jing Li ◽

Kewei Xu ◽

Hao Ding ◽

Qiaozhen Xi

Keyword(s):

Locomotor Activity ◽

Signaling Pathway ◽

Specific Inhibitor ◽

Underlying Mechanism ◽

Ethanol Consumption ◽

Diglycidyl Ether ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Tnf Α

Abstract Aims Increasing preclinical and clinical reports have demonstrated the efficacy of gabapentin (GBP) in treating alcohol use disorder (AUD). However, the mechanism of the effects of GBP in AUD is largely unknown. Herein, we sought to investigate the effect of GBP in a rat model of AUD and explore the underlying mechanism. Methods The intermittent access to 20% ethanol in a 2-bottle choice (IA2BC) procedure was exploited to induce high voluntary ethanol consumption in rats. The rats were treated daily for 20 days with different doses of GBP, simultaneously recording ethanol/water intake. The locomotor activity and grooming behavior of rats were also tested to evaluate the potential effects of GBP on confounding motor in rats. The levels of IL-1β and TNF-α in serum and hippocampus homogenate from the rats were detected by using ELISA. The expressions of peroxisome proliferator-activated-receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) in the hippocampus were determined by immunofluorescence and western blot. Results GBP reduced alcohol consumption, whereas increased water consumption and locomotor activity of rats. GBP was also able to decrease the levels of IL-1β and TNF-α in both serum and hippocampus, in addition to the expression of NF-κB in the hippocampus. Furthermore, these effects attributed to GBP were observed to disappear in the presence of bisphenol A diglycidyl ether (BADGE), a specific inhibitor of PPAR-γ. Conclusions Our findings revealed that GBP could activate PPAR-γ to suppress the NF-κB signaling pathway, contributing to the decrease of ethanol consumption and ethanol-induced neuroimmune responses.

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Peroxisome Proliferator-Activated ReceptorαReduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

Mediators of Inflammation ◽

10.1155/2016/5609121 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Hsu-Lung Jen ◽

Po-Len Liu ◽

Yung-Hsiang Chen ◽

Wei-Hsian Yin ◽

Jaw-Wen Chen ◽

...

Keyword(s):

Cell Size ◽

Underlying Mechanism ◽

Nuclear Factor Κb ◽

Cardiomyocyte Hypertrophy ◽

Peroxisome Proliferator ◽

Nuclear Factor ◽

Mobility Shift ◽

Peroxisome Proliferator Activated Receptor ◽

Human Cardiomyocytes ◽

Endothelin 1

Peroxisome proliferator-activated receptorα(PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARαactivation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARαactivator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARαwith adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARαexpression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARαcan decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.

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CXCL9 and CXCL11 Chemokines Modulation by Peroxisome Proliferator-Activated Receptor-α Agonists Secretion in Graves’ and Normal Thyrocytes

Endocrine Reviews ◽

10.1210/edrv.31.5.9998 ◽

2010 ◽

Vol 31 (5) ◽

pp. 780-780

Author(s):

Alessandro Antonelli ◽

Silvia Martina Ferrari ◽

Silvia Frascerra ◽

Cinzia Pupilli ◽

Caterina Mancusi ◽

...

Keyword(s):

Peroxisome Proliferator ◽

Rt Pcr ◽

Thyroid Cells ◽

Peroxisome Proliferator Activated Receptor ◽

Dependent Inhibition ◽

Pparγ Agonists ◽

Dose Dependent Inhibition ◽

And Control ◽

Dose Dependent

ABSTRACT Context Peroxisome proliferator-activated receptor (PPAR)-α has been shown to exert immunomodulatory effects in autoimmune disorders. However, until now, no data were present in the literature about the effect of PPARα activation on CXCL9 and CXCL11 chemokines in general or on secretion of these chemokines in thyroid cells. Objective and Design The presence of PPARα and PPARγ has been evaluated by RT-PCR in Graves’ disease (GD) and control cells in primary culture. Furthermore, we have tested the role of PPARα and PPARγ activation on CXCL9 and CXCL11 secretion in GD and control cells after stimulation of these chemokines secretion with IFNγ and TNFα. Results This study shows the presence of PPARα and PPARγ in GD and control cells. A potent dose-dependent inhibition by PPARα-agonists was observed on the cytokines-stimulated secretion of CXCL9 and CXCL11 in GD and control cells. The potency of the PPARα agonists used was maximum on the secretion of CXCL9, reaching about 90% of inhibition by fenofibrate and 85% by ciprofibrate. The relative potency of the compounds was different with each chemokine; for example, gemfibrozil exerted a 55% inhibition on CXCL11, whereas it had a weaker activity on CXCL9 (40% inhibition). PPARα agonists were stronger (ANOVA, P < 0.001) inhibitors of CXCL9 and CXCL11 secretion in thyrocytes than PPARγ agonists. Conclusions Our study shows the presence of PPARα in GD and control thyrocytes. PPARα activators are potent inhibitors of the secretion of CXCL9 and CXCL11, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

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Osthole Regulates TGF-β1 and MMP-2/9 Expressions via Activation of PPARα/γ in Cultured Mouse Cardiac Fibroblasts Stimulated with Angiotensin II

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3hk5c ◽

2013 ◽

Vol 16 (5) ◽

pp. 732 ◽

Cited By ~ 18

Author(s):

Rong Chen ◽

Jie Xue ◽

Meilin Xie

Keyword(s):

Angiotensin Ii ◽

Myocardial Fibrosis ◽

Transforming Growth Factor ◽

Cardiac Fibroblasts ◽

Underlying Mechanism ◽

Nuclear Factor Κb ◽

Peroxisome Proliferator ◽

Active Constituent ◽

Peroxisome Proliferator Activated Receptor ◽

Tgf Β1

PURPOSE. Our previous studies have demonstrated that osthole, an active constituent isolated from the fruit of Cnidium monnieri (L.) Cusson, can prevent isoprenaline-induced myocardial fibrosis in mice, but the underlying mechanism is still unclear. METHODS. The mouse cardiac fibroblasts (CFs) stimulated with angiotensin II (Ang II) were cultured and treated with different concentrations of osthole. The mRNA expressions of peroxisome proliferator-activated receptor (PPAR) α/γ, transforming growth factor β1 (TGF-β1), and matrix metalloproteinase (MMP)-2/9 were detected by reverse transcription polymerase chain reaction method, and the protein expressions of nuclear factor-κB (NF-κB) and TGF-β1 were detected by Western blot method, respectively. RESULTS. Following treatment of cells with osthole at 2.5, 5, 10 and 20 μg/mL, the NF-κB and TGF-β1 expressions were dose-dependently decreased, while the expressions of PPARα/γ and MMP-2/9 were dose-dependently increased. After the cells were preincubated with PPARα antagonist (MK886) or/and PPARγ antagonist (GW9662), the inhibitions of osthole on the NF-κB and TGF-β1 expressions were decreased or completely halted and the increment of osthole on the MMP-2/9 expressions were also decreased or completely cancelled. CONCLUSION. Osthole could inhibit the NF-κB and TGF-β1 expressions by activation of PPARα/γ, and subsequently enhance the MMP-2/9 expressions in cultured CFs, and these effects of osthole may play the beneficial roles in the prevention and treatment of myocardial fibrosis. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

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Adiponectin inhibits LPS-induced NF-κB activation and IL-6 production and increases PPARγ2 expression in adipocytes

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00397.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. R1220-R1225 ◽

Cited By ~ 208

Author(s):

Kolapo M. Ajuwon ◽

Michael E. Spurlock

Keyword(s):

Adipose Tissue ◽

Culture Media ◽

Elevated Serum ◽

Nuclear Factor Κb ◽

Interferon Γ ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Aortic Endothelial Cells ◽

Nuclear Extracts ◽

Tnf Α

Obesity and insulin resistance are often associated with lower circulating adiponectin concentrations and elevated serum interleukin-6 (IL-6) and/or tumor necrosis factor-α (TNF-α). Adiponectin suppresses activation of nuclear factor-κB (NF-κB) in aortic endothelial cells and porcine macrophages. Accordingly, we hypothesized that adiponectin is an anti-inflammatory hormone and suppresses activation of NF-κB in adipocytes. Because peroxisome proliferator-activated receptor γ2 (PPARγ2) antagonizes the transcriptional activity of NF-κB, we determined whether adiponectin alters PPARγ2 expression in pig adipocytes. In addition, we determined whether interferon-γ alters the expression of PPARγ2 in the presence or absence of adiponectin. Primary adipocytes from pig subcutaneous adipose tissue were treated with or without lipopolysaccharide (LPS; 10 μg/ml) and adiponectin (30 μg/ml), and nuclear extracts were obtained for gel shift assays to assess nuclear localization of NF-κB. Whereas LPS induced an increase in NF-κB activation, adiponectin suppressed both NF-κB activation and the induction of IL-6 expression by LPS ( P < 0.05). Similar results were obtained in 3T3-L1 adipocytes. In addition, adiponectin antagonized LPS-induced increase in TNF-α mRNA expression ( P < 0.05) and tended ( P < 0.065) to diminish its accumulation in the culture media in 3T3-L1 adipocytes. Adiponectin also induced an upregulation of PPARγ2 mRNA ( P < 0.05). Although IFN-γ did not reduce the basal expression of PPARγ2, it suppressed PPARγ2 induction by adiponectin ( P < 0.05). These findings indicate that adiponectin may be a local regulator of inflammation in the adipocyte and adipose tissue via its regulation of the NF-κB and PPARγ2 transcription factors.

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CXCL9 and CXCL11 Chemokines Modulation by Peroxisome Proliferator-Activated Receptor-α Agonists Secretion in Graves’ and Normal Thyrocytes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-0923 ◽

2010 ◽

Vol 95 (12) ◽

pp. E413-E420 ◽

Cited By ~ 45

Author(s):

Alessandro Antonelli ◽

Silvia Martina Ferrari ◽

Silvia Frascerra ◽

Cinzia Pupilli ◽

Caterina Mancusi ◽

...

Keyword(s):

Peroxisome Proliferator ◽

Thyroid Cells ◽

Peroxisome Proliferator Activated Receptor ◽

Dependent Inhibition ◽

Pparγ Agonists ◽

Dose Dependent Inhibition ◽

And Control ◽

Dose Dependent ◽

Stimulation Of

Context: Peroxisome proliferator-activated receptor (PPAR)-α has been shown to exert immunomodulatory effects in autoimmune disorders. However, until now, no data were present in the literature about the effect of PPARα activation on CXCL9 and CXCL11 chemokines in general or on secretion of these chemokines in thyroid cells. Objective and Design: The presence of PPARα and PPARγ has been evaluated by real-time-PCR in Graves’ disease (GD) and control cells in primary culture. Furthermore, we have tested the role of PPARα and PPARγ activation on CXCL9 and CXCL11 secretion in GD and control cells after stimulation of these chemokines secretion with IFNγ and TNFα. Results: This study shows the presence of PPARα and PPARγ in GD and control cells. A potent dose-dependent inhibition by PPARα-agonists was observed on the cytokines-stimulated secretion of CXCL9 and CXCL11 in GD and control cells. The potency of the PPARα agonists used was maximum on the secretion of CXCL9, reaching about 90% of inhibition by fenofibrate and 85% by ciprofibrate. The relative potency of the compounds was different with each chemokine; for example, gemfibrozil exerted a 55% inhibition on CXCL11, whereas it had a weaker activity on CXCL9 (40% inhibition). PPARα agonists were stronger (ANOVA, P < 0.001) inhibitors of CXCL9 and CXCL11 secretion in thyrocytes than PPARγ agonists. Conclusions: Our study shows the presence of PPARα in GD and control thyrocytes. PPARα activators are potent inhibitors of the secretion of CXCL9 and CXCL11, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

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Rosiglitazone Ameliorates Endotoxin-Induced Organ Damage in Conscious Rats

Biological Research For Nursing ◽

10.1177/1099800409353358 ◽

2009 ◽

Vol 13 (1) ◽

pp. 38-43 ◽

Cited By ~ 15

Author(s):

Wen-Tien Wu ◽

Chia-Chi Lee ◽

Chung-Jen Lee ◽

Yi-Maun Subeq ◽

Ru-Ping Lee ◽

...

Keyword(s):

Lactic Dehydrogenase ◽

Nuclear Factor Κb ◽

Organ Damage ◽

Endotoxin Shock ◽

Multiple Organ ◽

Organ Injury ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Conscious Rats ◽

Tnf Α

Rosiglitazone is a peroxisome proliferator-activated receptor (PPAR)-γ agonist. By inhibiting nuclear factor κB (NF-κB), it decreases tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) and has an anti-inflammatory effect. Endotoxin shock can induce the production of several inflammatory mediators such as TNF-α and IL-6, leading to multiple organ dysfunction and death. We investigated the effects of rosiglitazone (.3 mg/kg, intravenous administration) on the physiologic attributes and cytokine levels in endotoxin shock in conscious rats. Endotoxin shock was induced by intravenous injection of Klebsiella pneumoniae lipopolysaccharides (LPSs; 10 mg/kg) in conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 24 hr after LPS administration. Levels of biochemical and cytokine parameters, including glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), creatine phosphokinase (CPK), glucose, TNF-α, and IL-6 were measured at 0, 1, 3, 6, 12, and 24 hr after sepsis. Endotoxin shock significantly increased blood GOT, GPT, BUN, Cre, LDH, CPK, glucose, TNF-α, and IL-6 levels and HR, while also decreasing MAP. Rosiglitazone diminished the increase in HR, decreased the markers of organ injury (GOT, GPT, BUN, Cre, LDH, CPK, glucose) and inflammatory biomarkers (TNF-α, IL-6), and did not affect MAP after LPS. In conclusion, rosiglitazone ameliorated endotoxin shock-induced markers of organ injury and suppressed the release of TNF-α and IL-6 in conscious rats.

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The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22020934 ◽

2021 ◽

Vol 22 (2) ◽

pp. 934

Author(s):

Woon-Man Kung ◽

Muh-Shi Lin

Keyword(s):

Neurodegenerative Diseases ◽

Mitochondrial Dysfunction ◽

Management Strategies ◽

Nuclear Factor Κb ◽

Peroxisome Proliferator ◽

Proinflammatory Response ◽

Pharmacological Management ◽

Peroxisome Proliferator Activated Receptor ◽

Iron Sulfur ◽

Promising Target

Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs.

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