Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice

Abstract

Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and atherosclerosis. We have recently demonstrated that exposure of rodents to potent PPs indirectly causes a number of immunomodulating effects, resulting in severe adaptive immunosuppression. Since the peroxisome proliferator-activated receptor alpha (PPARα) plays a central role in mediating the pleiotropic responses exerted by PPs, we have compared here the immunomodulating effects of the PPs perfluorooctanoic acid (PFOA) and Wy-14,643 in wild-type and PPARα-null mice. The reductions in spleen weight and in the number of splenocytes caused by PP treatment in wild-type mice was not observed in PPARα-null mice. Furthermore, the reductions in thymus weight and in the number of thymocytes were potently attenuated in the latter animals. Similarly, the dramatic decreases in the size of the CD4⁺CD8⁺ population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of the cell cycle observed in wild-type mice administered PPs were much less extensive in PPARα-null mice. Finally, in contrast to the case of wild-type animals, the response of splenocytes isolated from the spleen of PP-treated PPARα-null mice to appropriate T- or B-cell activators in vitro was not reduced. Altogether, these data indicate that PPARα plays a major role in the immunomodulation caused by PPs. The possible relevance of these changes to the alterations in plasma lipids also caused by PPs is discussed.

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].