PPAR Research

PPAR Research / 2007 / Article

Research Article | Open Access

Volume 2007 |Article ID 049671 | https://doi.org/10.1155/2007/49671

Mostafa Z. Badr, Alexander Shnyra, Mikhail Zoubine, Maxim Norkin, Betty Herndon, Tim Quinn, Roberto N. Miranda, Michael L. Cunningham, Agostino Molteni, "Phthalate-Induced Liver Protection against Deleterious Effects of the Th1 Response: A Potentially Serious Health Hazard", PPAR Research, vol. 2007, Article ID 049671, 6 pages, 2007. https://doi.org/10.1155/2007/49671

Phthalate-Induced Liver Protection against Deleterious Effects of the Th1 Response: A Potentially Serious Health Hazard

Academic Editor: Saleh M. Ibrahim
Received08 Mar 2007
Accepted01 Jun 2007
Published01 Jan 2008

Abstract

Infection with Mycobacterium tuberculosis (TB) induces pulmonary immunopathology mediated by classical Th1 type of acquired immunity with hepatic involvement in up to 80% of disseminated cases. Since PPAR agonists cause immune responses characterized by a decrease in the secretion of Th1 cytokines, we investigated the impact of activating these receptors on hepatic pathology associated with a well-characterized model of Th1-type pulmonary response. Male Fischer 344 rats were either maintained on a drug-free diet (groups I and II), or a diet containing diethylhexylphthalate (DEHP), a compound transformed in vivo to metabolites known to activate PPARs, for 21 days (groups III and IV). Subsequently, animals were primed with Mycobacterium bovis purified protein derivative (PPD) in a Complete Freund's Adjuvant. Fifteen days later, animals in groups II and IV were challenged with Sepharose 4B beads covalently coupled with PPD, while animals in groups I and III received blank Sepharose beads. Animals with Th1 response (group II) showed a marked structural disruption in the hepatic lobule. Remarkably, these alterations were conspicuously absent in animals which received DEHP (group IV), despite noticeable accumulation of T cells in the periportal triads. Immunostaining and confocal microscopy revealed hepatic accumulation of IFNγ+ Th1 and IL-4+ Th2 cells in animals from groups II and IV, respectively. Our data suggest a PPARα-mediated suppression of the development of a Th1 immune response in the liver, resulting in hepatoprotective effect. However, potentially negative consequences of PPAR activation, such as decreased ability of the immune system to fight infection and interference with the efficacy of vaccines designed to evoke Th1 immune responses, remain to be investigated.

References

  1. C. Levine, “Primary macronodular hepatic tuberculosis: US and CT appearances,” Gastrointestinal Radiology, vol. 15, no. 1, pp. 307–309, 1990. View at: Publisher Site | Google Scholar
  2. B. Qiu, K. A. Frait, F. Reich, E. Komuniecki, and S. W. Chensue, “Chemokine expression dynamics in mycobacterial (type-1) and schistosomal (type-2) antigen-elicited pulmonary granuloma formation,” American Journal of Pathology, vol. 158, no. 4, pp. 1503–1515, 2001. View at: Google Scholar
  3. S.-L. Tsai, Y.-F. Liaw, M.-H. Chen, C.-Y. Huang, and G. C. Kuo, “Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity,” Hepatology, vol. 25, no. 2, pp. 449–458, 1997. View at: Publisher Site | Google Scholar
  4. H. Tsutsui, K. Adachi, E. Seki, and K. Nakanishi, “Cytokine-induced inflammatory liver injuries,” Current Molecular Medicine, vol. 3, no. 6, pp. 545–559, 2003. View at: Google Scholar
  5. 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: Publisher Site | Google Scholar
  6. A. E. Lovett-Racke, R. Z. Hussain, S. Northrop et al., “Peroxisome proliferator-activated receptor a agonists as therapy for autoimmune disease,” Journal of Immunology, vol. 172, no. 9, pp. 5790–5798, 2004. View at: Google Scholar
  7. R. Kleemann, P. P. Gervois, L. Verschuren, B. Staels, H. M.G. Princen, and T. Kooistra, “Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation,” Blood, vol. 101, no. 2, pp. 545–551, 2003. View at: Publisher Site | Google Scholar
  8. J. Youssef and M. Z. Badr, “Biology of senescent liver peroxisomes: role in hepatocellular aging and disease,” Environmental Health Perspectives, vol. 107, no. 10, pp. 791–797, 1999. View at: Publisher Site | Google Scholar
  9. W. Klöpffer, “Environmental hazard, assessment of chemicals and products—Part II: persistence and dependability of organic chemicals,” Environmental Science and Pollution Research, vol. 1, pp. 108–116, 1994. View at: Google Scholar
  10. T. J. Wams, “Diethylhexylphthalate as an environmental contaminant—a review,” Science of the Total Environment, vol. 66, pp. 1–16, 1987. View at: Publisher Site | Google Scholar
  11. W. W. Huber, B. Grasl-Kraupp, and R. Schulte-Hermann, “Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in rodents and its implications on human risk,” Critical Reviews in Toxicology, vol. 26, no. 4, pp. 365–481, 1996. View at: Google Scholar
  12. L. Castle, A. Mayo, and J. Gilbert, “Migration of plasticizers from printing inks into foods,” Food Additives and Contaminants, vol. 6, no. 4, pp. 437–443, 1989. View at: Google Scholar
  13. B. C. Blount, M. J. Silva, S. P. Caudill et al., “Levels of seven urinary phthalate metabolites in a human reference population,” Environmental Health Perspectives, vol. 108, no. 10, pp. 979–982, 2000. View at: Publisher Site | Google Scholar
  14. J. J. Adibi, F. P. Perera, W. Jedrychowski et al., “Prenatal exposures to phthalates among women in New York and Krakow, Poland,” Environmental Health Perspectives, vol. 111, no. 14, pp. 1719–1722, 2003. View at: Google Scholar
  15. E. K. Maloney and D. J. Waxman, “trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals,” Toxicology and Applied Pharmacology, vol. 161, no. 2, pp. 209–218, 1999. View at: Publisher Site | Google Scholar
  16. A. Molteni, B. Herndon, A. Kamal et al., “Effect of the antioxidant a-tocopherol in an experimental model of pulmonary hypertension and fibrosis: administration of monocrotaline,” Nutrition Research, vol. 24, no. 9, pp. 707–720, 2004. View at: Publisher Site | Google Scholar
  17. S.-R. Shi, R. J. Cote, and C. R. Taylor, “Antigen retrieval immunocytochemistry: past, present, future,” Journal of Histochemistry and Cytochemistry, vol. 45, no. 3, pp. 327–343, 1997. View at: Google Scholar
  18. J. Youssef and M. Z. Badr, “Aging and enhanced hepatocarcinogenicity by peroxisome proliferator- activated receptor alpha agonists,” Ageing Research Reviews, vol. 4, no. 1, pp. 103–118, 2005. View at: Publisher Site | Google Scholar
  19. F. Rahman, T. Heller, Y. Sobao et al., “Effects of antiviral therapy on the cellular immune response in acute hepatitis C,” Hepatology, vol. 40, no. 1, pp. 87–97, 2004. View at: Publisher Site | Google Scholar
  20. F. Magro, P. Pereira, F. Carneiro, and F. T. Veloso, “Reactive hepatitis in a patient with Crohn's disease succcessfully treated with infliximab: does tumor necrosis factor alpha play a role in reactive hepatitis?” Inflammatory Bowel Diseases, vol. 11, no. 1, pp. 88–90, 2005. View at: Publisher Site | Google Scholar
  21. N. K. Dhillon, Y. Sui, R. Potula et al., “Inhibition of pathogenic SHIV replication in macaques treated with antisense DNA of interleukin-4,” Blood, vol. 105, no. 8, pp. 3094–3099, 2005. View at: Publisher Site | Google Scholar
  22. J. Youssef and M. Z. Badr, “Extraperoxisomal targets of peroxisome proliferators: mitochondrial, microsomal, and cytosolic effects. Implications for health and disease,” Critical Reviews in Toxicology, vol. 28, no. 1, pp. 1–33, 1998. View at: Publisher Site | Google Scholar
  23. C.-J. Wu, L.-C. Chen, and M.-L. Kuo, “Attenuated salmonella typhimurium reduces ovalbumin-induced airway inflammation and T-helper type 2 responses in mice,” Clinical and Experimental Immunology, vol. 145, no. 1, pp. 116–122, 2006. View at: Publisher Site | Google Scholar

Copyright © 2007 Mostafa Z. Badr et al. 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.


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