Inhibition of carrageenan-induced cutaneous inflammation by PPAR agonists is dependent on hepatocyte-specific retinoid X receptor alpha

Yu-Jui Yvonne Wan, Mostafa Z. Badr

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11 Citations (Scopus)

Abstract

It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRα on the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARα agonist perfluorooctanoic acid diminished carrageenan-induced paw edema by 66±10%. This effect was essentially absent (13±8%) in hepatocyte-specific RXRα-deficient mice. Similarly, pretreatment of WT mice with the PPARδ agonist L-783483 or the PPARγ agonist L-805645 caused 54±1% and38±8% reduction in carrageenan-induced paw edema,respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRα-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRα-deficient mice.The identification of RXRα as an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.

Original languageEnglish (US)
Article number96341
JournalPPAR Research
DOIs
StatePublished - 2006
Externally publishedYes

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Retinoid X Receptor alpha
Peroxisome Proliferator-Activated Receptors
Carrageenan
Hepatocytes
Inflammation
Skin
Edema
perfluorooctanoic acid
Retinoid X Receptors
Inhibition (Psychology)
Aspirin
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Drug Discovery

Cite this

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title = "Inhibition of carrageenan-induced cutaneous inflammation by PPAR agonists is dependent on hepatocyte-specific retinoid X receptor alpha",
abstract = "It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRα on the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARα agonist perfluorooctanoic acid diminished carrageenan-induced paw edema by 66±10{\%}. This effect was essentially absent (13±8{\%}) in hepatocyte-specific RXRα-deficient mice. Similarly, pretreatment of WT mice with the PPARδ agonist L-783483 or the PPARγ agonist L-805645 caused 54±1{\%} and38±8{\%} reduction in carrageenan-induced paw edema,respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRα-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRα-deficient mice.The identification of RXRα as an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.",
author = "Wan, {Yu-Jui Yvonne} and Badr, {Mostafa Z.}",
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N2 - It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRα on the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARα agonist perfluorooctanoic acid diminished carrageenan-induced paw edema by 66±10%. This effect was essentially absent (13±8%) in hepatocyte-specific RXRα-deficient mice. Similarly, pretreatment of WT mice with the PPARδ agonist L-783483 or the PPARγ agonist L-805645 caused 54±1% and38±8% reduction in carrageenan-induced paw edema,respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRα-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRα-deficient mice.The identification of RXRα as an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.

AB - It has been proposed that PPAR-dependent, accelerated catabolism of proinflammatory mediators may contribute to the fast resolution of inflammation. Because retinoid X receptors are obligate heterodimer partners of PPARs, we investigated the impact of deleting hepatocyte-specific RXRα on the antiedema effect of PPAR agonists. In wild-type mice (WT), pretreatment with the PPARα agonist perfluorooctanoic acid diminished carrageenan-induced paw edema by 66±10%. This effect was essentially absent (13±8%) in hepatocyte-specific RXRα-deficient mice. Similarly, pretreatment of WT mice with the PPARδ agonist L-783483 or the PPARγ agonist L-805645 caused 54±1% and38±8% reduction in carrageenan-induced paw edema,respectively. These effects were also significantly diminished or absent in hepatocyte-specific RXRα-deficient mice. In contrast, aspirin reduced carrageenan-induced paw edema equally in WT and hepatocyte-specific RXRα-deficient mice.The identification of RXRα as an important factor involved in the antiedema effect produced by agonists of the three PPAR subtypes is a significant achievement towards the goal of designing novel, effective anti-inflammatory drugs.

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