The Journal of Immunology, 2005, 175: 4777-4782.
Copyright © 2005 by The American Association of Immunologists
Induction of Apoptosis by the Hydrocarbon Oil Pristane: Implications for Pristane-Induced Lupus1
Nicola Calvani*,
Roberto Caricchio
,
Marco Tucci*,
Eric S. Sobel
,
Franco Silvestris*,
Paola Tartaglia* and
Hanno B. Richards2,
* Department of Internal Medicine and Clinical Oncology, University of Bari, Bari, Italy;
Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Florida, Gainesville, FL 32610
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Abstract
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Intraperitoneal injection of the hydrocarbon oil pristane into normal mice leads to a lupus-like autoimmune syndrome. Although advances in defining the roles of cellular and humoral mediators involved in this syndrome have been made, the mechanisms that initiate a break in tolerance leading to autoimmunity remain unknown. We describe in this study that pristane induces apoptosis both in vivo and in vitro. Pristane arrests cell growth and induces cell death by apoptosis via the mitochondrial pathway of caspase activation in a dose-dependent manner. Nuclear autoantigens created by pristane-induced apoptosis of lymphoid cells within the peritoneal cavity in the setting of a profoundly altered cytokine milieu may be the initiating event in the development of autoimmunity in this syndrome. These findings suggest that apoptosis may be a critical initial event in the pathogenesis of pristane-induced lupus and are of potential relevance for human systemic lupus erythematosus.
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Introduction
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Dysregulation of apoptosis and altered clearance of apoptotic cells have been linked to the development of autoimmunity (1). Both genetic and environmental triggers can induce apoptosis (2), contributing to an increased amount of apoptotic material found specifically in systemic lupus erythematosus (SLE),3 such as circulating nucleosomes (3). Lupus-like autoimmunity can be induced in normal mice by i.p. injection of pristane (2,6,10,14-tetramethylpentadecane) (4). This model is well suited to investigate the role of environmental factors that may predispose to the development of SLE and allows for study of the initial events that lead to a break in tolerance in the absence of genetic defects.
We have previously reported that autoantibody production occurs in pristane-induced lupus via a T cell-dependent immune response in which nucleoprotein complexes act as self-Ags (5). However, the precise mechanism by which pristane induces a break in tolerance, and how intracellular targets become antigenic remain to be defined. Pristane is a membrane-active compound that has been shown to interact with phospholipid bilayers and cell membranes. It has been reported to have a cytotoxic effect dependent on concentration and cell line (6), although the mechanism of this cytotoxicity remains unknown.
Because apoptosis has emerged in recent years to explain how self-Ags might become available to a self-primed immune system (7), the aim of this study was to examine the potential role of pristane in the initiation of apoptosis in lymphoid cell lines and in murine peritoneal exudate cells. We report in this study that pristane induces programmed cell death both in vitro and in vivo. We speculate that apoptosis brought about by pristane provides the autoantigen substrate necessary for a break in tolerance, ultimately leading to the development of lupus-like autoimmunity.
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Materials and Methods
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Cells and culture conditions
BW5147 (murine), Jurkat (human T cell lymphoma), and U266 (human myeloma) cells were obtained from American Type Culture Collection. Freshly isolated peritoneal cells from mice were used in some experiments. Cells were grown in DMEM supplemented with 10% FBS under standard cell culture conditions. Due to its insolubility in aqueous medium, pristane (Sigma-Aldrich) was added as a suspension of inclusion complexes with 
-cyclodextrin (-CyD; Sigma-Aldrich) as previously described (6).
Treatment of mice
Female BALB/cJ, B6, B6 lpr/lpr (The Jackson Laboratory), and BALB/cAn (National Cancer Institute) mice housed under specific pathogen-free conditions, aged 6–8 mo, were used to analyze pristane-induced apoptosis in vivo in most experiments. For the experiments to characterize specific cell populations (as shown in Fig. 5), four 12-wk-old B6 mice housed under conventional conditions were used. Animals were injected once i.p. with either 0.5 ml of pristane or PBS. After 48 h, peritoneal cells were collected by lavage and depleted of RBC by lysis.
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FIGURE 5. FACS plots showing the accumulation of DCs in the peritoneal cavity of mice treated with pristane compared with that in mice given PBS. Depicted is the profile of lymphoid and myeloid DCs after gating on class II+ events: PBS vs pristane lymphoid DCs, 1.7 vs 5.5%; PBS vs pristane myeloid DCs, 5.1 vs 24.3%.
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FACS analysis
Apoptosis was assessed and quantified by staining for annexin V-PE, 7-aminoactinomycin (7AAD), and rabbit mAb anti-active caspase 3-FITC according to the manufacturer’s protocols (BD Pharmingen). Peritoneal cells were stained using rat anti-mouse mAbs. For T cell staining, the following combination was used: CD90.2-FITC, annexin V-PE, 7AAD, CD4-B/Av-Pacific Blue, CD3-allophycocyanin, and CD8a-allophycocyanin-Cy7. For B cell staining, annexin V-PE, 7AAD, CD5-B/Av-Pacific Blue, IgM-allophycocyanin, and B220-allophycocyanin-Cy7 were used. For dendritic cells (DCs) and monocytes, I-A(b)-FITC, annexin V-PE, 7AAD, CD11c-B/Av-Pacific Blue, CD11b-allophycocyanin, and B220-allophycocyanin-Cy7 were used. All the reagents were purchased from BD Pharmingen, with the exception of the apoptosis kit (annexin and 7AAD) and avidin-Pacific Blue (Molecular Probes). Samples were analyzed with a DakoCytomation Cyan flow cytometer. Each analysis included a total of at least 10,000 events.
Detection of mRNA expression for Fas and Fas ligand (Fas-L)
Total RNA was isolated, reverse transcribed, and amplified using the ThermoScript RT-PCR System according to the instructions of the manufacturer (Invitrogen Life Technologies). Amplification conditions were 94°C for 30 s, 56°C for 30 s, and 72°C for 30 s. Thirty cycles with a final extension of 10 min at 72°C were performed in a thermocycler (MJ Research). -Actin served as a control. Amplification products were analyzed on agarose gels by ethidium bromide staining. Primer sequences for mouse Fas, Fas-L, and -actin were used as previously described (8).
Cytochrome c release assay
Cells were fixed (1% paraformaldehyde, 10 min), permeabilized (0.3% Saponin, 5 min), and incubated in blocking buffer (PBS with 3% BSA). After washing, cells were incubated with mouse anti-cytochrome c mAb (BD Pharmingen) in blocking buffer, washed three times, and incubated with rhodamine-conjugated goat anti-mouse IgG (Jackson ImmunoResearch Laboratories). Finally, cells were transferred on slides, coverslips were mounted, and fluorescence images were examined. Cells were examined with an immunofluorescence microscope (Olympus BX60; Olympus Optical) with x40 objectives. Images were collected with a CCD camera (Sensys; Photometric) and processed with IPLab software (Scanalytic).
Inhibition of caspase activity
Caspase 8 and 9 activities were inhibited by treating the cells for 1 h with Ac-ESMD-CHO (Alexis) or Ac-LHD-CHO (Alexis), respectively. Inhibitors were dissolved in DMSO and added at a final concentration of 20 µM. Thereafter, 200 µM pristane was added to the culture medium for 36 h. Cells were then harvested and evaluated for apoptosis by annexin V labeling. Control experiments used untreated cells as well as cells incubated with DMSO alone.
Statistical analysis
Difference between groups were determined by the Mann-Whitney U test.
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Results
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Pristane induces apoptosis in lymphoid cell lines in a time- and dose-dependent manner
BW5147 cells were incubated with various concentrations of pristane (up to 400 µM) for up to 48 h. After different time intervals, cells were harvested and stained with annexin V-PE and 7AAD. One of the earlier events during cell death is externalization of membrane phospholipid phosphatidylserine (PS) (9). Annexin V is a phospholipid-binding protein with a high affinity for PS and binds to cells with exposed PS. 7AAD allows for differentiation between early apoptotic cells that stain positively for annexin V but negatively for 7AAD (membrane integrity still present) and nonviable cells that are positive for both annexin V and 7AAD (10). The number of early apoptotic cells (annexin V+/7AAD–) progressively increased between 24 and 48 h of pristane treatment, becoming significantly higher by 48 h compared with untreated control cells (60 ± 1.3 vs 6.2 ± 1%; p < 0.05; Figs. 1 and 2A, pristane vs no treatment). Apoptosis was also measured by detection of the active form of caspase 3 an executor protease that is a marker for cells undergoing apoptosis (11). Markedly higher levels of active caspase 3 were found after 48 h in pristane-treated cells compared with untreated cells (46 ± 5.9 vs 6 ± 1.3%; p < 0.05; Fig. 2B, pristane vs no treatment). Finally, changes in the morphology of apoptotic cells were monitored as a change in light-scattering properties (12). After pristane treatment, cells shifted toward a lower forward (reduction in size) and higher side scatter (increase in granularity), a pattern typical for apoptotic cells (Fig. 2C, pristane vs no treatment). To control for any potential effect of -CyD, we also incubated cells with -CyD alone (400 µM). We found no difference between cells treated with -CyD alone compared with untreated cells. To examine a possible effect of a mineral oil contained within inclusion complexes between -CyD, we incubated cells with mineral oil and another alkane, n-hexadecane. Neither mineral oil (data not shown) nor n-hexadecane complexed with -CyD induced apoptosis (Fig. 2). Pristane also induced apoptosis in Jurkat and U266 cells, albeit at slightly lower levels (data not shown). We also examined the dose-response relationship for the induction of apoptosis by pristane. Fig. 3A shows that concentrations of 100 µM or more were required to increase the percentage of annexin V+/7AAD– cells significantly (p < 0.05) compared with no treatment.
Pristane treatment is associated with apoptosis of murine peritoneal cells both in vitro and in vivo
For the induction of a lupus-like syndrome, a single dose of 0.5 ml of pristane (2 mM) was injected i.p. Although the oil was taken up by tissue relatively rapidly, pristane could still be found in significant quantities in the peritoneal fluid for months. Peritoneal cells were thus exposed to pristane over a prolonged period of time and may therefore be subject to its apoptotic properties. To substantiate this premise in an ex vivo approach, fresh cells collected from the peritoneal cavity of normal mice were cultured with pristane (200 µM) for different intervals of time. Not surprisingly, after 48 h, viable cells (annexin V-PE–/7AAD–) were dramatically reduced with pristane treatment (Fig. 3B), and we found mostly dead cells that stained with both annexin V-PE and 7AAD (not shown). However, the presence of a distinct annexin V-PE+/7AAD– subpopulation and activation of caspase 3 suggested that peritoneal cells had undergone cell death by apoptosis, rather than necrosis secondary to pristane treatment (not shown). Furthermore, time-course experiments revealed that these cells underwent apoptosis by 6 h of pristane treatment (Fig. 3C).
Next, we investigated the effect of pristane treatment in vivo. Freshly isolated peritoneal cells from several common strains of mice were obtained 48 h after treatment with either PBS or pristane (without -CyD). As shown in Fig. 3D, pristane induced apoptosis, as shown by both annexin V and active caspase 3 staining. In a subsequent experiment, 6- to 8-mo-old B6 mice were injected with either pristane (n = 7) or PBS (n = 7). After 48 h, the number of apoptotic cells in the peritoneal lavage was significantly higher in pristane-treated mice than in control mice, as determined by caspase 3 cleavage (18.2 ± 1.2 vs 2.7 ± 0.9%; p < 0.05; Fig. 4A) and annexin V binding (Fig. 4B). To further define which cell populations were affected by pristane, pooled peritoneal cells from 12-wk-old B6 mice 48 h after treatment with either pristane or PBS were analyzed by FACS. As shown in Table I both conventional B cells (B2) and B1 cells were more sensitive to pristane-induced apoptosis (annexin V+/7AAD–) than either CD4+ or CD8+ T cells. Neither activated (I-A(b)+) nor nonactivated (I-A(b)–) peritoneal monocytes (CD11b+) appeared to be affected by pristane (Table I), whereas markedly increased apoptosis was observed in both myeloid (CD11c+/CD11b+) and lymphoid (CD11c+/CD11b–) DCs (Table I). Interestingly a relative accumulation of DCs was observed in pristane-treated mice, with an increase in CD11c+/CD11b+ cells from 5.1 to 24.3% and in CD11c+/CD11b– cells from 1.7 to 5.5% (Fig. 5).
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FIGURE 4. Pristane-induced apoptosis is present in vivo. The representative FACS diagrams show active caspase 3 staining (A) and annexin V/7AAD staining (B) in peritoneal cells freshly isolated from 6- to 8-mo-old B6 mice 48 h after pristane vs PBS treatment. Similar results were obtained for a total of seven pristane-treated mice and seven PBS-treated mice.
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Pristane induces apoptosis via the mitochondrial pathway
In characterizing the molecular events leading to apoptosis through pristane exposure, we found that mRNA transcription for Fas and Fas-L were up-regulated in peritoneal cells from pristane-treated mice compared with those from PBS-treated mice (Fig. 6A). Results were analogous to those observed in BW5147 cells after pristane administration in vitro (Fig. 6A). However, cells lacking a functional Fas pathway, such as those from B6 lpr/lpr mutant mice, were also sensitive to pristane-induced apoptosis in vitro (data not shown) and in vivo (Fig. 6B), suggesting that apoptosis brought about by pristane could occur independently of Fas. Thus, we examined whether the mitochondrial pathway was involved in pristane-induced apoptosis. We detected the release of cytochrome c in BW5147 cells induced to undergo apoptosis by pristane (Fig. 7, A and B), suggesting that the mitochondrial pathway is involved in pristane-induced apoptosis. To further explore the importance of the mitochondrial pathway in pristane-induced apoptosis we conducted experiments to specifically block caspases 8 and 9. As shown in Fig. 7C, pristane-induced apoptosis in BW5147 cells was effectively blocked by the addition of a specific inhibitor of caspase 9 (Ac-LHD-CHO). In contrast, apoptosis was not affected by the addition of a specific inhibitor of caspase 8 (ESMD-CHO; Fig. 7C).
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FIGURE 6. A, RNA was extracted from BW5147 after either no treatment or treatment with pristane for 48 h and analyzed for Fas and Fas-L expression by RT-PCR. To examine in vivo effects of pristane on Fas/Fas-L, RNA was extracted from freshly isolated peritoneal cells from BALB/cJ mice 48 h after treatment with either PBS (n = 4) or pristane (n = 4) and analyzed by RT-PCR. Results for each individual mouse are shown. B, Pristane induces apoptosis in B6 lpr/lpr mice in vivo. The representative FACS diagrams show annexin V/7AAD staining in peritoneal cells freshly isolated from B6 lpr/lpr mice 48 h after pristane (n = 3) vs PBS (n = 3) treatment.
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FIGURE 7. Pristane induces apoptosis via the mitochondrial pathway. In untreated BW5147 cells, cytochrome c is contained within the mitochondrial compartment, as demonstrated by the punctate staining in A. In contrast, after pristane treatment (200 µM for 18 h), cells released cytochrome c by showing diffuse cytoplasmic and nuclear staining, as shown in B. C, Pristane-induced apoptosis in BW5147 was effectively blocked by the addition of a specific inhibitor of caspase 9 (Ac-LHD-CHO). However, apoptosis was not affected by the addition of a specific inhibitor of caspase 8 (ESMD-CHO). The bars represent the mean percentage and SD of apoptotic cells (annexin V+/7AAD–) from five different experiments. The dashed line indicates the mean percentage of apoptosis for cells treated with DMSO alone. *, p < 0.05, by Mann-Whitney U test.
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Discussion
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To examine the potential mechanisms by which a lupus-like syndrome is induced in normal mice by pristane, we investigated the potential of this hydrocarbon oil to induce apoptosis. To our knowledge this is the first report that pristane induces cell death by apoptosis. To substantiate our findings, we made use of several different techniques for the detection of programmed cell death both in vivo and in vitro: detection of annexin V binding to exposed PS (10), measurement of caspase 3 activation (11), cytochrome c release (13), and evaluation of changes in cell morphology (12). We demonstrate in this study that pristane is a powerful inducer of apoptosis in cultured lymphoid cells, such as BW5147, Jurkat, and U266, and in freshly isolated murine peritoneal cells. We confirm that pristane-induced apoptosis, in our in vitro experiments, is not due to -CyD alone or a -CyD emulsion containing another hydrocarbon oil, such as hexadecane, because no apoptosis was induced under either of these culture conditions (Fig. 2).
We report that pristane induces apoptosis in murine peritoneal cells in vivo, thus providing a potential mechanism by which a break in self tolerance may occur in pristane-induced lupus. In particular, we hypothesize that autoantigens exposed through apoptosis induced by pristane and exposed to APCs in the setting of a milieu within the peritoneal cavity that is saturated with inflammatory mediators (14) may be the triggering event leading to autoimmunity. The fact that membrane blebs of apoptotic bodies are potential sources of autoantigens (15), including major pathogenic lupus autoantigens (16, 17, 18), strongly supports this hypothesis. Moreover, we report that both myeloid and lymphoid DCs are disproportionately affected by pristane to undergo apoptosis (Table I), and that these cells are present in high numbers in the peritoneal cavity of pristane-treated mice (Fig. 5). The reasons for the preferential recruitment of DCs to the peritoneal cavity by pristane and their high apoptotic susceptibility to his hydrocarbon oil remain unclear. We speculate that DCs may be relatively more responsive to both chemotactic mediators and inflammatory cytokines than T cells and especially monocytes, and that B cells show intermediate responses to these stimuli produced by resident peritoneal cells after exposure to pristane. Potentially, there may be differences in transmembrane transport of pristane or permeability to this oil among DCs, B cells, T cells, and monocytes, which may explain their differential susceptibilities to undergo apoptosis.
DCs are uniquely equipped to capture endogenous apoptotic cells and present self-Ags to Th cells (19). This may be especially relevant in settings of excessive cellular apoptosis in which the scavenger system becomes overwhelmed and an atypical reservoir of self-Ag is established (20). In support of this scenario are the mouse models in which the subversion of apoptotic clearance mechanisms leads to lupus-like manifestations (1). Of particular interest is the MFG-E8 (milk fat globulin epidermal growth factor 8) mutant mouse in which engulfment of apoptotic cells is impaired in germinal centers (21).
Mineral oil or other alkanes, such as n-hexadecane, are not associated with the development of an SLE-like disease when administered to mice (22). We show in this study that an alkane similar to pristane does not induce apoptosis (Fig. 2), suggesting that there are specific properties of pristane not shared by similar hydrocarbons that lead to apoptosis and ultimately autoimmunity. Mevorach et al. (23) reported that i.v. administration of syngeneic apoptotic lymphocytes was capable of inducing autoantibody production in normal mice. However, after a single injection, autoantibody levels were found to be low and appeared only transiently, indicating that exposure to apoptotic cells alone is not sufficient for sustained autoimmunity. In contrast, pristane administered i.p. is widely distributed throughout the mouse and is detectable for a prolonged time period within the peritoneal cavity and other organs (24), thus allowing for sustained exposure to immune-competent cells. Indeed, we have found increased apoptosis in peritoneal exudate cells from mice 10 mo after injection of pristane compared with that in mice treated with PBS (data not shown). This lends support to the idea that ongoing autoantigen exposure secondary to pristane-induced apoptosis may be operative for the maintenance of a sustained autoimmune response.
In experiments studying pristane-treated B6 lpr mice, it has been reported that pristane exposure and defective Fas signaling act on different pathways of autoantibody formation, probably as a consequence of different cytokine requirements (25). Accordingly, our data indicate that pristane-induced apoptosis can occur in the absence of Fas and appears to involve the mitochondrial pathway of caspase activation. However, the early events following the exposure of cells to pristane finally leading to cytochrome c release remained to be defined, and it is unclear whether pristane mediates its effects through a cellular receptor. In studies using nuclear magnetic resonance imaging of pristane uptake into lipid bilayers, it has been shown that pristane localizes to the hydrophobic compartment of the cell membrane (26). It is therefore conceivable that pristane may induce its early apoptotic effects by an indirect, passive, nonreceptor-mediated mechanism, causing changes in the biophysical properties of the membrane bilayers. However, one would expect that other alkanes, such as n-hexadecane, should effect similar cellular changes as pristane, but it did not. The dose-response curve of induction of apoptosis by pristane is sigmoidal and saturable, with a peak at 
300 µM (Fig. 3), which is akin to many receptor-mediated events and argues for the potential existence of a receptor for this hydrocarbon oil.
In conclusion, we present evidence that pristane arrests cell growth and induces cell death by apoptosis in lymphoid cell lines as well as in murine peritoneal cells both in vitro and in vivo. These findings present a potential explanation for the mechanism by which pristane induces autoimmunity. We speculate that uptake of autoantigens provided by sustained apoptosis in the setting of an inflammatory milieu leads to a break in self tolerance and ultimately autoimmunity.
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Disclosures
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The authors have no financial conflict of interest.
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Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Grant NIDDK K08DK02890-02 (to H.B.R.) and Arthritis Investigator Award (to R.C.). 
2 Address correspondence and reprint requests to Dr. Hanno B. Richards, Division of Rheumatology and Clinical Immunology, P.O. Box 100221, 1600 SW Archer Road, University of Florida, Gainesville, FL 32610-0221. E-mail address: richahb{at}medicine.ufl.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; 7AAD, 7-aminoactinomycin; -CyD, -cyclodextrin; DC, dendritic cell; Fas-L, Fas ligand; PS, phosphatidylserine.
Received for publication September 24, 2004.
Accepted for publication July 25, 2005.
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Abstract
Introduction
