Inhibition of Carrageenan-Induced Cutaneous Inflammation by PPAR
Agonists Is Dependent on Hepatocyte-Specific Retinoid X Receptor
<i>Alpha</i>

Wan, Yu-Jui Yvonne; Badr, Mostafa Z.

doi:https://doi.org/10.1155/PPAR/2006/96341

PPAR Research

On this page

Abstract References Copyright Related Articles

Research Article | Open Access

Volume 2006 | Article ID 096341 | https://doi.org/10.1155/PPAR/2006/96341

Inhibition of Carrageenan-Induced Cutaneous Inflammation by PPAR Agonists Is Dependent on Hepatocyte-Specific Retinoid X Receptor Alpha

Yu-Jui Yvonne Wan¹and Mostafa Z. Badr²

Received30 Jan 2006

Revised20 Apr 2006

Accepted21 Apr 2006

Published04 Jul 2006

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% and 38±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.

References

H S Camp, O Li, S C Wise et al., “Differential activation of peroxisome proliferator-activated receptor- $\gamma$ by troglitazone and rosiglitazone,” Diabetes, vol. 49, no. 4, pp. 539–547, 2000.
View at: Google Scholar
A Chawla, Y Barak, L Nagy, D Liao, P Tontonoz, and R M Evans, “PPAR- $\gamma$ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation,” Nature Medicine, vol. 7, no. 1, pp. 48–52, 2001.
View at: Google Scholar
R Cunard, M Ricote, D DiCampli et al., “Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors,” Journal of Immunology, vol. 168, no. 6, pp. 2795–2802, 2002.
View at: Google Scholar
S Cuzzocrea, R Di Paola, E Mazzon et al., “Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR- $\alpha$ ) in the development of inflammatory bowel disease in mice,” Laboratory Investigation, vol. 84, no. 12, pp. 1643–1654, 2004.
View at: Google Scholar
S Cuzzocrea, N S Wayman, E Mazzon et al., “The cyclopentenone prostaglandin 15-deoxy- $\Delta ^{12,14}$ -prostaglandin ${\text{J}}_2$ attenuates the development of acute and chronic inflammation,” Molecular Pharmacology, vol. 61, no. 5, pp. 997–1007, 2002.
View at: Google Scholar
S T De Dios, K M Hannan, R J Dilley, M A Hill, and P J Little, “Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells,” Journal of Diabetes and Its Complications, vol. 15, no. 3, pp. 120–127, 2001.
View at: Google Scholar
P R Devchand, H Keller, J M Peters, M Vazquez, F J Gonzalez, and W Wahli, “The PPAR $\alpha$ -leukotriene B4 pathway to inflammation control,” Nature, vol. 384, no. 6604, pp. 39–43, 1996.
View at: Google Scholar
Y Hattori, S Hattori, and K Kasai, “Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells,” Hypertension, vol. 33, no. 4, pp. 943–948, 1999.
View at: Google Scholar
D J Mangelsdorf and R M Evans, “The RXR heterodimers and orphan receptors,” Cell, vol. 83, no. 6, pp. 841–850, 1995.
View at: Google Scholar
L A Moraes, L Piqueras, and D Bishop-Bailey, “Peroxisome proliferator-activated receptors and inflammation,” Pharmacology & Therapeutics, vol. 110, no. 3, pp. 371–385, 2006.
View at: Google Scholar
R Mukherjee, J Strasser, L Jow, P Hoener, J R Jr Paterniti, and R A Heyman, “RXR agonists activate PPAR $\alpha$ -inducible genes, lower triglycerides, and raise HDL levels in vivo,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no. 2, pp. 272–276, 1998.
View at: Google Scholar
B K Taylor, N Dadia, C B Yang, S Krishnan, and M Z Badr, “Peroxisome proliferator-activated receptor agonists inhibit inflammatory edema and hyperalgesia,” Inflammation, vol. 26, no. 3, pp. 121–127, 2002.
View at: Google Scholar
B K Taylor, C Kriedt, S Nagalingam, N Dadia, and M Z Badr, “Central administration of perfluorooctanoic acid inhibits cutaneous inflammation,” Inflammation Research, vol. 54, no. 6, pp. 235–242, 2005.
View at: Google Scholar
Y-J Y Wan, D An, Y Cai et al., “Hepatocyte-specific mutation establishes retinoid X receptor $\alpha$ as a heterodimeric integrator of multiple physiological processes in the liver,” Molecular and Cellular Biology, vol. 20, no. 12, pp. 4436–4444, 2000.
View at: Google Scholar
Y-J Y Wan, Y Cai, W Lungo et al., “Peroxisome proliferator-activated receptor $\alpha$ -mediated pathways are altered in hepatocyte-specific retinoid x receptor $\alpha$ -deficient mice,” Journal of Biological Chemistry, vol. 275, no. 36, pp. 28285–28290, 2000.
View at: Google Scholar
J Youssef and M Z Badr, “Role of peroxisome proliferator-activated receptors in inflammation control,” Journal of Biomedicine and Biotechnology, vol. 2004, no. 3, pp. 156–166, 2004.
View at: Google Scholar

Copyright

Copyright © 2006 Yu-Jui Yvonne Wan and Mostafa Z. Badr. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation Order printed copies