PPAR‐gamma modulates allergic inflammation through up‐regulation of PTEN

Lee, Kyung S.; Park, Seoung J.; Hwang, Pyoung Han; Yi, Ho Keun; Song, Chang Ho; Chai, Ok Hee; Kim, Jong‐Suk; Lee, Moon K.; Lee, Yong C.

doi:10.1096/fj.04-3309fje

Cited by 119 publications

(132 citation statements)

References 42 publications

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“…Additionally, pharmacological affinity studies have previously shown that of the 4 TZD's, Rosi has the highest affinity for PPARg, followed by Pioglitazone > Troglitazone > Ciglitazone. 29,30 Previously, PPARg agonists, in particular Rosi, have been shown to correlate with PTEN expression in MCF-7 breast cancer cells, 18 macrophages, 18 monocytes, 44 bronchoalveolar lavage cells 45 and AsPC-1 pancreatic cancer cells. 46 We show here that stimulation of MCF-7 cells with 30 lM Rosi results in a~1.5-fold increase in PTEN.…”

Section: Discussionmentioning

confidence: 99%

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Teresi

Shaiu

Chen

et al. 2006

Intl Journal of Cancer

107

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Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARc has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARc binding site in the PTEN promoter indicates that PPARc may regulate PTEN expression. We show here that the PPARc agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose-and time-dependent manner. Lovastatin-or Rosiglitazoneinduced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin-and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARc, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARc-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARc, that both Lovastatin and Rosiglitazone specifically mediate PPARc activation. Additionally, we demonstrated that cells lacking PTEN or PPARc were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARc and directly demonstrate that PPARc can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. ' 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Teresi

Shaiu

Chen

et al. 2006

Intl Journal of Cancer

107

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“…Rosiglitazone (1, 2.5, or 5 mg/kg body weight/day; GlaxoSmithKline) dissolved in distilled water or pioglitazone (1, 5, or 10 mg/kg body weight/ day; Takeda Chemical Industries) dissolved in 0.05% DMSO and diluted with saline, was administered by oral gavage at 24-h interval on days 36 -66, beginning 2 days before the first challenge as previously described (15) (Fig. 1).…”

Section: Administration Of Rosiglitazone Pioglitazone Gw9662 Ad Vementioning

confidence: 99%

“…1). A selective antagonist of PPAR␥, GW9662 (0.5 mg/kg body weight/day; Cayman) dissolved in PBS was administered intratracheally six times to each animal on days 37,40,47,54,61, and 67, beginning 1 day before the first challenge as previously described (15). Ad vectors were administered intratracheally (10 9 PFU) six times to each animal on days 37, 40, 47, 54, 61, and 65, beginning 1 day before the first challenge.…”

Section: Administration Of Rosiglitazone Pioglitazone Gw9662 Ad Vementioning

confidence: 99%

“…Protein expression levels were analyzed by Western blot analysis, as described previously (15). The blots were incubated with an anti-IL-4 Ab (Serotec), anti-IL-5 Ab (Santa Cruz Biotechnology), anti-IL-13 Ab (R&D Systems), anti-TGF-␤1 Ab (Santa Cruz Biotechnology), anti-ICAM-1 Ab (Santa Cruz Biotechnology), anti-VCAM-1 Ab (Santa Cruz Biotechnology), anti-RANTES Ab (Abcam), anti-eotaxin Ab (Abcam), anti-Akt Ab (Cell Signaling Technology), and anti-phosphorylated Akt (p-Akt) Ab (Cell Signaling Technology).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Cytosolic or nuclear extractions for analysis of NF-B p65 and PPAR␥ were performed as described previously (15). The levels of these proteins were analyzed by Western blotting using Ab against NF-B p65 (Upstate Biotechnology) or PPAR␥ (Santa Cruz Biotechnology).…”

Section: Cytosolic or Nuclear Protein Extractions For Analysis Of Nf-mentioning

confidence: 99%

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Modulation of Airway Remodeling and Airway Inflammation by Peroxisome Proliferator-Activated Receptor γ in a Murine Model of Toluene Diisocyanate-Induced Asthma

Lee¹,

Park²,

Kim³

et al. 2006

The Journal of Immunology

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Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to play a critical role in the control of airway inflammatory responses. However, no data are available on the role of PPARγ in TDI-induced asthma. We have used a mouse model for TDI-induced asthma to determine the effect of PPARγ agonist, rosiglitazone, or pioglitazone, and PPARγ on TDI-induced bronchial inflammation and airway remodeling. This study with the TDI-induced model of asthma revealed the following typical pathophysiological features: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased levels of Th2 cytokines (IL-4, IL-5, and IL-13), adhesion molecules (ICAM-1 and VCAM-1), chemokines (RANTES and eotaxin), TGF-β1, and NF-κB in nuclear protein extracts. In addition, the mice exposed to TDI developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer, subepithelial collagen deposition, and increased airway mucus production. Administration of PPARγ agonists or adenovirus carrying PPARγ2 cDNA reduced the pathophysiological symptoms of asthma and decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, TGF-β1, and NF-κB in nuclear protein extracts after TDI inhalation. In addition, inhibition of NF-κB activation decreased the increased levels of Th2 cytokines, adhesion molecules, chemokines, and TGF-β1 after TDI inhalation. These findings demonstrate a protective role of PPARγ in the pathogenesis of the TDI-induced asthma phenotype.

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Immunotoxicogenomics: A Systems Approach

Vandebriel

Loveren

Baken

et al. 2009

General, Applied and Systems Toxicology

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Immunotoxicity can be defined as the adverse effects of toxicants on the immune system. Low‐molecular‐weight chemicals that are able to induce allergy can be divided into contact and respiratory sensitizers. These sensitizers differ not only in their relevant exposure routes and the clinical effects they can induce, but also in risk assessment. Various types of data suggest that the oxidative stress response pathway is the most significant one affected by contact sensitizer exposure. Less abundant, primarily toxicogenomics, data suggest that the PTEN pathway is the most significant pathway affected by respiratory sensitizer exposure. The chemical characteristics that determine whether a sensitizer is a contact or respiratory sensitizer are beginning to be understood. We hypothesize how the oxidative stress and PTEN pathways may result in the in vivo observations of preferential Th1 and Th2 responses by contact and respiratory sensitizers, respectively. While for contact sensitization risk assessment seems to be feasible, this prospect is still remote for respiratory sensitization, partly because a validated in vivo model and quantitative data are lacking. To be able to identify respiratory sensitizers, we propose to develop non‐animal assays on the basis of human data. This proposition also holds for risk assessment of respiratory sensitization. We anticipate that development of non‐animal assays as well as risk assessment will depend on a systems toxicology framework.

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PPAR‐gamma modulates allergic inflammation through up‐regulation of PTEN

Cited by 119 publications

References 42 publications

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Modulation of Airway Remodeling and Airway Inflammation by Peroxisome Proliferator-Activated Receptor γ in a Murine Model of Toluene Diisocyanate-Induced Asthma

Immunotoxicogenomics: A Systems Approach

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