Lipids and lipid metabolism have well-documented regulatory effects on inflammatory processes. Recent work has highlighted the role of the peroxisome proliferator-activated receptors (PPARs)--a subset of the nuclear-hormone-receptor superfamily that are activated by various lipid species--in regulating inflammatory responses. Here, we describe how the PPARs, through their interactions with transcription factors and other cell-signalling systems, have important regulatory roles in innate and adaptive immunity.

In aged mice, the redox-regulated transcription factor nuclear factor-B (NF-B) becomes constitutively active in many tissues, as well as in cells of the hematopoietic system. This oxidative stress-induced activity promotes the production of a number of pro-inflammatory cytokines, which can contribute to the pathology of many disease states associated with aging. The administration to aged mice of agents capable of activating the ␣ isoform of the peroxisome proliferator-activated receptor (PPAR␣) was found to restore the cellular redox balance, evidenced by a lowering of tissue lipid peroxidation, an elimination of constitutively active NF-B, and a loss in spontaneous inflammatory cytokine production. Aged animals bearing a null mutation in PPAR␣ failed to elicit these changes following treatment with PPAR␣ activators, but remained responsive to vitamin E supplementation. Aged C57BL/6 mice were found to express reduced transcript levels of PPAR␣ and the peroxisomeassociated genes acyl-CoA oxidase and catalase. Supplementation of these aged mice with PPAR␣ activators or with vitamin E caused elevations in these transcripts to levels seen in young animals. Our results suggest that PPAR␣ and the genes under its control play a role in the evolution of oxidative stress excesses observed in aging.

Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone produced in abundance by humans and most other warm-blooded animals, is uniquely sulfated (DHEAS) prior to export into the plasma, and exhibits an age-related decline in production with progressive age. No major physiological functions have been ascribed to the activity of this steroid, although DHEA is known to serve as an intermediary in sex steroid synthesis. Studies on the effects of glucocorticoids (GCS) on the immune system led us to question whether DHEA had effects on the ability of activated lymphocytes to produce interleukin 2 (IL 2). We determined that (a) lymphocytes from DHEA- or DHEAS-treated mice consistently produced much greater levels of IL 2 than normals in response to stimulation, (b) direct lymphocyte exposure to DHEA at low doses (10(-10)-10(-7) M) caused an enhanced capacity to secrete IL 2 following activation, (c) IL 2 production by activated cloned T cell lines could be augmented by DHEA treatment, and (d) GCS-induced depressions in IL 2 synthesis by T cells or T cell clones could be overcome in vitro and in vivo by exposure to the effects of DHEA. These findings suggest that DHEA, presumably through receptor-mediated mechanisms similar to other types of steroid hormones, may represent a natural and important regulator of IL 2 production in both normal and pathologic conditions.

The molecular mechanisms which govern the biosynthesis and secretion of the various T cell-derived lymphokines are poorly understood at this time, in spite of their tremendous importance to the control of the mammalian immune system. Here we provide compelling evidence that production of the murine T cell growth factors interleukin (IL) 2 and IL4 are differentially regulated by glucocorticoid (GCS) hormones. Under conditions where IL2 production is reduced by GCS hormones, IL4 production is increased. In vivo, this effect on T cell production of growth factors is manifest at low GCS concentrations that are well within physiologic ranges. In vitro, splenocytes isolated from antigen-stimulated donors, as well as antigen-specific cloned T cell lines, undergo alterations in their capacity to secrete T cell growth factors when stimulated with antigens in the presence of GCS. Responses normally dominated by IL2 are dramatically shifted to a condition where IL4 represents the major species of T cell growth factor produced. Similar changes in the pattern of T cell growth factor production are observed following short pulses with low-dose GCS in vitro, and the steroid-induced depression in IL2 production can be reversed and/or inhibited by treatment with the potent steroid antagonist RU486. Our results imply that GCS hormones, presumably through their capacity to activate a specified family of ligand-dependent transcriptional regulatory proteins (steroid hormone receptors), function to control the pattern of lymphokines produced by activated T cells. Steroid-mediated regulation of lymphokine gene expression could serve to dictate the types of immune effector mechanisms which can be initiated subsequent to antigen exposure.