Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice
Introduction
Peroxisome proliferators constitute a very large (>1000 at present) and growing family of wide-spread foreign compounds, including numerous industrial chemicals (e.g. plasticizers such as phthalates and surfactants such as perfluoro fatty acids), agrochemicals (e.g. pesticides such as phenoxyacetic acids) and important clinical drugs (e.g. nonsteroidal anti-inflammatory drugs such as acetylsalicylic acid and hypolipidemic agents such as fibrate derivatives) [1], [2]. The most extensively characterized effects of PPs on susceptible animal species are increases in the number and size of hepatic peroxisomes, together with potent transcriptional up-regulation of the levels of hepatic fatty acid-metabolizing enzymes and hepatomegaly. Furthermore, prolonged treatment of rodents with peroxisome proliferators results in an increased incidence of liver tumors [2], [3].
There is presently an increasing awareness that direct or indirect interactions of xenobiotics (drugs and other foreign chemicals) with the immune system may result in extensive immunomodulation [4], [5]. Such changes in the immune system caused by xenobiotics may contribute to an increased incidence and/or severity of infection, increased immunoreactivity towards environmental agents (hypersensitivity) and/or enhanced tumor development [6]. Recently, it has been demonstrated in our laboratory that PPs cause potent immunomodulating effects in mice, involving thymic and splenic atrophy, loss of thymocytes and splenocytes, and potent suppression of adaptive immune responses [7], [8], [9]. The mechanism(s) underlying these phenomena are at present unclear.
The peroxisome proliferator-activated receptors (PPARs), form a subfamily of the nuclear receptors superfamily, along with the receptors for thyroid hormone, retinoid acid and Vitamin D. The α isoform of PPAR is well known to be involved in mediating many of the adaptive responses of rodents to exposure to PPs [3], [10], [11], [12]. In rodents, PPARα is expressed at relatively high levels in the liver, kidney and heart, all of which display peroxisome proliferation in response to PPs and are characterized by high rates of lipid metabolism [13]. Transgenic mice which are homozygous with regards to a functional mutation in the PPARα gene do not demonstrate peroxisome proliferation, hepatomegaly or hepatocarcinogenesis, even after chronic exposure to PPs [14], [15]. Therefore, the current study was designed to examine the possible involvement of PPARα in the immunomodulation exerted by PPs. For this purpose, PFOA was employed as the model PP, since this compound is not metabolized in mice [16], [17], [18] and is one of the most potent PPs presently known. In addition, immunomodulation by PFOA has been previously characterized in some detail in our laboratory [7], [8], [9].
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Animals and treatment
All experiments were performed on adult male C57Bl/6 (wild-type; obtained from B&K Universal AB, Sweden) or PPARα-null mice of a pure Sv/129 genetic background (derived from the original colony of mixed background mice [12]; kindly provided by Frank Gonzalez). Animals weighing 22–25 g (about 8–10 weeks old) were randomly divided into groups of four and housed in steel cages with a 12-hr light/dark cycle at 25° and free access to water and laboratory chow (Rat and Mouse Standard Diet, B&K
General observations during administration of PFOA or Wy-14,643 to wild-type or PPARα-null mice
In comparison to wild-type animals, PPARα-null mice exhibit normal thymus and spleen weights and normal numbers of thymocytes and splenocytes (Table 1). Dietary administration of PFOA or Wy-14,643 to wild-type mice for 7 days resulted in a significant decrease in body weight; but no such change was observed in the case of PPARα-null mice (Table 1). This is in agreement with observations using another PP, DEHP, which also significantly reduces the body weight of wild-type, but not of PPARα-null
Discussion
Although PPARα-null mice are unresponsive to PPs, their phenotype is normal in most other respects [14], [15]. The normal thymus and spleen weights and cell numbers, as well as the normal in vitro responses of splenocytes to T- or B-cell activators indicate that PPAR-null mice have a normal immune system. At the same time, the small, but significant increases in the CD4+CD8+ population of thymocytes and the increased number of thymocytes in the S–G/M phase of the cell cycle may indicate that
Acknowledgements
The Knut and Alice Wallenberg Foundation (Stockholm) and the Environmental Fund of the Swedish Association of Graduate Engineers (Stockholm) provided financial support for this investigation. We are also grateful to Jarl Olsson for his help with the animals.
References (39)
Peroxisome proliferation: current mechanisms relating to nongenotoxic carcinogenesis
Toxicol. Lett.
(1995)- et al.
Further evidence for the involvement of inhibition of cell proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator perfluorooctanoic acid in mice
Biochem. Pharmacol.
(2001) - et al.
Potent suppression of the adaptive immune response in mice upon dietary exposure to the potent peroxisome proliferator, perfluorooctanoic acid
Int. Immunopharmacol.
(2002) - et al.
Disposition of perfluorodecanoic acid in male and female rats
Toxicol. Appl. Pharmacol.
(1991) - et al.
Determination of peroxisomal fatty acyl-CoA oxidase activity using a lauroyl-CoA-based fluorometric assay
Biochim. Biophys. Acta
(1986) - et al.
A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry
J. Immunol. Methods
(1991) - et al.
Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha)
J. Biol. Chem.
(1998) - et al.
Promotion of human T lymphocyte activation and proliferation by fatty acids in low density and high density lipoproteins
J. Biol. Chem.
(1986) - et al.
Lipoproteins may provide fatty acids necessary for human lymphocyte proliferation by both low density lipoprotein receptor-dependent and -independent mechanisms
J. Biol. Chem.
(1989) - et al.
Membrane compartmentation and the response to antigen
Curr. Opin. Immunol.
(1999)
Perfluorooctanoic acid, a peroxisome-proliferating hypolipidemic agent, dissociates apolipoprotein B48 from lipoprotein particles and decreases secretion of very low density lipoproteins by cultured rat hepatocytes
Biochim. Biophys. Acta
Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences
Arch. Toxicol.
Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators
Annu. Rev. Pharmacol. Toxicol.
Immunotoxicity of pesticides: a review
Toxicol. Ind. Health
Chemical agents and the immune response
Environ. Health Perspect.
Effects of peroxisome proliferators on the thymus and spleen of mice
Clin. Exp. Immunol.
Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology
Annu. Rev. Cell Dev. Biol.
Peroxisome proliferator-activated receptors: nuclear control of metabolism
Endocr. Rev.
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