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

Knethen, Andreas von; Soller, Mathias; Tzieply, Nico; Weigert, Andreas; Johann, Axel M.; Jennewein, Carla; Köhl, Roman; Brüne, Bernhard

doi:10.1084/jem2043oia5

Cited by 8 publications

(10 citation statements)

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“…This was accomplished by NFκB reporter assays in RAW264.7 d/n PPARγ macrophages overexpressing various deletion constructs of DsRed-tagged PPARγ1, that were previously verified for their expression by Western blot analysis (18). The DsRed-PPARγ1 wild-type encoding vector was included as a control.…”

Section: Resultsmentioning

confidence: 99%

“…The following day cells were treated with AC for 90 min, followed by stimulation with 1 μg/ml LPS for 1 h. Cell lysis and Western blot analysis was performed as described (18). An anti-PPARγ antibody (1:2000, H100-X from Santa Cruz Biotechnology, Inc., Heidelberg, Germany) and anti-β-tubulin (1:1000, Sigma-Aldrich, Deisenhofen, Germany) were used.…”

Section: Methodsmentioning

confidence: 99%

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Sumoylation of Peroxisome Proliferator-Activated Receptor γ by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from κB Binding Sites Mediating Transrepression of Proinflammatory Cytokines

Jennewein

Kühn

Schmidt

et al. 2008

The Journal of Immunology

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105

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R ecognition of apoptotic cells (AC)3 elicits immunological consequences that have received considerable attention during recent years. Professional phagocytes such as dendritic cells and macrophages recognize AC via so called "eat me" signals, with concomitant phagocytosis (1). The uptake of AC avoids secondary necrosis and thus the release of harmful cell contents. Moreover, ingestion of apoptotic material actively provokes a macrophage phenotype shift, which helps to terminate perpetuating inflammatory responses. The altered macrophage phenotype is characterized by the release of antiinflammatory mediators such as TGF-␤ or prostaglandin E 2 (2). Additionally, these polarized macrophages suppress the production of reactive oxygen species (3), NO (4), and proinflammatory cytokines such as TNF-␣, IL-1␤, and IL-6 (1). AC block NF-B activation, which contributes to the diminished production of proinflammatory cytokines, although mechanisms of how NF-B is inhibited remain unclear (5). Cvetanovic and Ucker demonstrated that an attenuated NF-B transactivation response and an AC-elicited reduction in target gene expression are cell-cell contact-dependent but phosphatidylserine-independent (6). Furthermore, it was noticed that NF-B binding to DNA as well as IB degradation were not affected by AC. As an alternative explanation, it was proposed that a limited amount of p300, an established co-factor of NF-B-dependent proinflammatory gene expression (7), decreases its activity, although underlying mechanisms remain obscure (5). A potential candidate known to interact with p300 and thereby attenuating an inflammatory response is peroxisome proliferatoractivated receptor ␥ (PPAR␥) (8).PPAR␥ belongs to the nuclear hormone receptor superfamily of ligand-activated transcription factors and originally has been characterized to be important for adipogenesis and glucose metabolism (9). Induction of PPAR␥ target genes requires ligand binding, heterodimerization with the retinoid X receptor (RXR), and subsequent binding to specific peroxisome proliferator response elements. Besides transcriptional activation, PPAR␥ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.1 This work was supported by grants from Deutsche Forschungsgemeinschaft (Br 999, FOG 784, Excellence Cluster Cardiopulmonary System), Deutsche Krebshilfe, Sander Foundation, LiFF, and European Community (PROLIGEN).2 Address correspondence and reprint requests to Dr. Bernhard Brüne, Goethe-University Frankfurt am Main, Faculty of Medicine, Institute of Biochemistry I/Zentrum für Arzneimittelforschung, -Entwicklung und -Sicherheit (ZAFES), Pathobiochemistry, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail address: bruene@ zbc.kgu.de 3 Abbreviations used in this paper: AC, apoptotic cells; ChIP, chromatin immunoprecipitation; d/n, dominant negative; HDAC, histone deacetylase; iNOS, inducible NO s...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Sumoylation of Peroxisome Proliferator-Activated Receptor γ by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from κB Binding Sites Mediating Transrepression of Proinflammatory Cytokines

Jennewein

Kühn

Schmidt

et al. 2008

The Journal of Immunology

Self Cite

105

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“…Because NRs are present in the nucleus, the precise mechanism through which they affect components in the cytoplasm (e.g., 22‐( R )‐HC and/or 9cRA‐mediated inhibition of STAT1 phosphorylation and activation) remains to be determined. It should be noted that NR such as PPARγ have been found to shuttle from the nucleus to the cytoplasm [Von Knethen et al, 2007, 2010]. It is therefore possible that such NR in the cytoplasm affects the IFN‐γ‐induced STAT1 phosphorylation or there is transcriptional activation of a cytoplasmic protein that mediates the inhibitory action of the NR.…”

Section: Discussionmentioning

confidence: 99%

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

Salter

Ramji

2011

J of Cellular Biochemistry

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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.

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“…While this pathway remains speculative in the case of PPARβ/δ, others have shown that PPARγ receptors bind and repress PKCα in human nucleated cells (Paumelle et al. , 2006; von Knethen et al. , 2007).…”

Section: Ppars: Mechanism Of Actionmentioning

confidence: 99%

Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease

Belvisi

Mitchell

2009

British J Pharmacology

105

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. PPARg regulates several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of genes involved in lipid biosynthesis and glucose metabolism. However, more recently PPARg, PPARa and PPARb/d agonists have been demonstrated to exhibit anti-inflammatory and immunomodulatory properties thus opening up new avenues for research. The actions of PPARg and PPARa activation are thought to be due to their ability to down regulate pro-inflammatory gene expression and inflammatory cell functions, and as such makes them an attractive target for novel drug intervention. Interestingly, PPARb/d has been shown to be involved in wound healing, angiogenesis, lipid metabolism and thrombosis. In this review we will focus on the data describing the beneficial effects of these ligands in the airway and in the pulmonary vasculature and in vivo in animal models of allergic and occupational asthma, chronic obstructive pulmonary disease and pulmonary fibrosis. A clinical trial is underway to examine the effect of rosiglitazone in asthma patients and the outcome of this trial is awaited with much anticipation. In conclusion, PPARs are novel targets for lung disease and continued work with these ligands may result in a potential new treatment for chronic inflammatory lung diseases.

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

Cited by 8 publications

References 1 publication

Sumoylation of Peroxisome Proliferator-Activated Receptor γ by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from κB Binding Sites Mediating Transrepression of Proinflammatory Cytokines

Sumoylation of Peroxisome Proliferator-Activated Receptor γ by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from κB Binding Sites Mediating Transrepression of Proinflammatory Cytokines

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

Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease

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