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Cells1
Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907-1264
2To whom correspondence should be addressed. E-mail: teegarden{at}cfs.purdue.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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fibroblast cells. Apoptosis induced by the ceramide analog, C8-ceramine, was inhibited by S1P (ceramine/S1P). Stress activated protein kinase or c-Jun N-terminal kinase (SAPK/JNK) activation was significantly higher after ceramine and ceramine/S1P treatments. Ceramine/S1P treatment also significantly increased ERK activation and MKP-1 protein levels. ERK activation was required for the inhibition of apoptosis by S1P as shown using the mitogen-activated protein kinase kinase inhibitor, PD98059. Transfection with a dominant negative mutant construct of the MKP-1 gene prevented S1P inhibition of apoptosis and resulted in sustained SAPK/JNK activity. The MKP-1 mutant did not affect ERK activity, indicating that MKP-1 preferentially down-regulates SAPK/JNK in C3H10T cells. Finally, the S1P activation of ERK and inhibition of apoptosis were reduced by pertussis toxin treatment, suggesting that G-protein–coupled receptors, such as the endothelial differentiation gene (EDG) receptor, play a role. Thus, both ERK activation and MKP-1, which down-regulates SAPK/JNK, are required for S1P-mediated inhibition of apoptosis.
KEY WORDS: • apoptosis • mitogen-activated protein kinase • mitogen-activated protein kinase phosphatase • sphingosine-1-phosphate • ceramide • extracellular regulated kinase
Sphingolipids are significant dietary components, which possess promising anticancer properties (1,2). The sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P)2 are important lipid signaling molecules (3,4). Stimuli such as tumor necrosis factor (TNF)-
, interleukin-1ß, 1,25-dihydroxyvitamin D3 or ionizing radiation degrade sphingomyelin, producing ceramide via the action of sphingomyelinases (5,6). Once formed, ceramide has been shown to initiate apoptosis through the activation of the stress-activated protein kinase or c-Jun N-terminal kinase (SAPK/JNK), a member of the mitogen-activated protein kinase (MAPK) family (7–9). The mouse embryonic fibroblast cell line, C3H10T, is resistant to apoptotic induction by C8-ceramide, and the metabolism of exogenous ceramide to S1P is critical to cell survival (10). Thus, this cell line provides an interesting model with which to study both endogenous and exogenous S1P regulation of apoptosis.
S1P, a ceramide metabolite, is a specific ligand for several members of the G-protein–coupled endothelial differentiation gene (EDG) receptor family (11). Stimulation by S1P through the EDG receptors was shown to activate extracellular signal-regulated protein kinase (ERK), also a MAPK family member (12). S1P was also shown to activate ERK through EDG receptor independent mechanisms (13) and to inhibit ceramide-induced apoptosis through the activation of ERK (14). Thus, ceramide and S1P may exert opposing actions within cells via differential regulation of MAPK family members (8,15).
MAPK phosphorylate and activate downstream targets such as transcription factors and regulators of cell growth and differentiation (16). The MAPK family members include the ERK, p44 MAPK (ERK1) and p42 MAPK (ERK2); the SAPK or JNK, p54 SAPK/ß/JNK 2 and p45 SAPK
/JNK1; and the p38 MAPK (, ß, ß II, and 
) (17). The activity of both ERK and SAPK/JNK is regulated by reversible phosphorylation of tyrosine and threonine residues located within the activation lip of the protein. The ERK pathway is activated by growth and mitogenic factors and functions in cell proliferation, differentiation and/or cell survival. The SAPK/JNK pathway, on the other hand, is activated by stress factors such as cytokines and UV radiation and functions in differentiation, growth arrest and initiation of apoptosis (8). The balance between ERK and SAPK/JNK activation has been proposed to be an important determinant of cell survival or cell death (18).
The mitogen-activated protein kinase phosphatases (MKP), a family of proteins that includes MKP-1, dephosphorylate and down-regulate all members of the MAPK family (19). There are currently nine distinct MKP family members that have been cloned, and most are the products of immediate early genes (19,20). Activation of both ERK and SAPK/JNK has been associated with an increase in MKP-1 expression, suggesting a role for MKP-1 in the down-regulation of the activated kinases by dephosphorylation in a feedback mechanism (21,22). A variety of factors, including retinoids (23), glucocorticoids (24) and a range of stress factors have been shown to act by stimulating an increase in MKP expression, and subsequent down-regulation of MAPK. Therefore, the purpose of this investigation was to determine the role of MKP-1 in S1P inhibition of apoptosis.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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C8-ceramide, C8-ceramine and sphingosine-1-phosphate were from Biomol (Plymouth Meeting, PA). Ceramide and ceramine were dissolved in 100% ethanol and an appropriate amount from a stock solution was added directly to the cultured cells to yield the desired final concentration of compounds (ethanol < 3% final concentration). S1P was dissolved in 70% ethanol. A stock solution for S1P was then made in 1% fatty acid–free bovine serum (FBS) albumin in PBS (137 mmol/L sodium chloride, 1.5 mmol/L potassium phosphate, 7.2 mmol/L sodium phosphate, 2.7 mmol/L potassium chloride, pH 7.4). An appropriate amount of the stock solution was then added to the cultured cells to yield the desired final concentration of S1P. DMEM, FBS, and penicillin and streptomycin were purchased from Life Technologies, Gibco BRL (Rockville, MD). Reagents used for apoptosis analysis were purchased from Boehringer Mannheim (Indianapolis, IN). Phosphorylation-specific and nonphosphorylation-specific antibodies to ERK1/2 and SAPK/JNK, and the Phototope-Star Chemiluminescent Detection Kit were obtained from New England Biolabs (Beverly, MA). Antibodies to MKP-1 and actin were from Santa Cruz Biotechnologies (Santa Cruz, CA).
Expression constructs.
pCEP4CS, containing dominant negative MKP-1, was from Dr. N. Tonks (Cold Spring Harbor Laboratory, NY). The dominant negative MKP-1 mutant has a cysteine replaced by a serine in the protein as described by Sun et al. (20). The inactive kinase SAPK/JNK construct, containing a K55A substitution, was from Dr. G. Johnson (University of Colorado Health Science Center, Denver, CO) (25). The inactive kinase SAPK/JNK construct was subcloned into pcDNA3 via BamH1, to generate pcDNA3S/J.
Cell culture.
C3H10T mouse fibroblast cells (CCL-226) were used in all experiments. Cells were grown in DMEM with 10% FBS, 100 U/mL penicillin, and 0.1 g/L streptomycin at 37°C in a humidified atmosphere of 5% CO2/95% O2 air. All experiments were performed with cells in linear growth.
ERK1/2 and SAPK/JNK activities.
To assess both ERK and SAPK/JNK activities, the cells were plated at 195,000 cells/dish for 2 d in 100-mm culture dishes; 48 h after plating, cells were treated with 10 µmol/L C8-ceramine (a nonmetabolizable analog of ceramide), 5 µmol/L S1P or with a combination of 10 µmol/L C8-ceramine and 5 µmol/L S1P for the indicated times. Ceramine has an amine bond in place of the amide bond of ceramide. Biochemical analysis of ceramine demonstrated that it is a weak competitive inhibitor of the enzyme ceramidase (26). Upon harvesting, both adherent and nonadherent cells were collected. Nonadherent cells were centrifuged at 447 x g for 5 min. The cell pellet was washed twice with calcium/magnesium-free PBS (CMF-PBS, (137 mmol/L sodium chloride, 1.5 mmol/L potassium phosphate, 7.2 mmol/L sodium phosphate, 2.7 mmol/L potassium chloride, pH 7.4). Adherent cells were washed with CMF-PBS. Cell pellets and adherent cells were then recombined and harvested directly into 5X sample buffer [62 mmol/L Tris (pH 6.8), 10% glycerol, 3% SDS, 5% ß-mercaptoethanol, and 0.002% bromophenol blue] and sonicated for 10 s. Proteins were separated by SDS-polyacrylamide gel electrophoresis, with equal volumes loaded for each lane of sample, and transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA). Membranes were probed with activation specific antibodies to either phospho-SAPK/JNK or phospho-ERK1/2 at 1:1000 dilution. Bands were visualized by chemiluminescence using horseradish peroxidase–conjugated anti-rabbit IgG. Bands were quantified by scanning with a Hewlett-Packard ScanJet4C scanner (Cincinnati, OH) used in conjunction with Kodak ds ID digital science v. 2.0.1 (Eastman Kodak, New Haven, CT). Doublet bands were quantified together. After visualization, membranes were stripped (stripping buffer; 100 mmol/L ß-mercaptoethanol, 2% SDS, 62.5 mmol/L Tris-HCl, pH 6.7) at 50°C for 30 min and reprobed with antibodies to total SAPK/JNK or total ERK. Bands were visualized and quantified as described. For each sample, the phosphorylated forms of SAPK/JNK and ERK were normalized to total levels of SAPK/JNK and ERK and then to the vehicle control time point. Data are expressed as fold increase in SAPK/JNK or ERK activity over time 0.
MKP-1 immunoblotting.
Cell extracts used for ERK1/2 and SAPK/JNK activities also were used to assess MKP-1 protein levels. Proteins were separated by SDS-polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes (Bio-Rad) and probed with a 1:1000 dilution of monoclonal antibody to MKP-1. Membranes were stripped as described above and reprobed with a monoclonal anti-actin antibody at a 1:2000 dilution. For each sample, MKP-1 values were normalized to actin. Data are expressed as fold increase in MKP-1 protein levels over time 0.
Assessment of apoptosis.
C3H10T cells were plated at 105,000 cells/dish in 100-mm culture dishes; 36 h after plating, cells were treated as described above for 12 h. Upon harvesting, both adherent and nonadherent cells were collected as described previously. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay was performed as described by Gorczyca et al. (27). Briefly, cells were fixed with 1% formaldehyde CMF-PBS. Cellular DNA strand breaks were labeled in situ with biotinylated dUTP via exogenous terminal deoxynucleotide transferase. DNA was costained with propidium iodide. Photographs of stained cells were taken using a Nikon Labphoto fluorescent microscope with an optronic cooled CCD camera (Nikon, Lewisville, TX).
In addition to the TUNEL assay, apoptosis was measured using the Cell Death Detection ELISA plus system (Boehringer Mannheim), a spectrophotometric enzyme-immunoassay for the in vitro determination of cytoplasmic histone-associated DNA-fragments of mono- and oligonucleosomes after induced cell death (10,28–30). At 36 h after plating, cells were treated and apoptosis assessed as directed by manufacturer’s instructions. Data are expressed as an enrichment factor (absorbance at 405 nm of each sample over the absorbance at 405 nm of the vehicle control).
MEK1 inhibitor apoptosis studies.
Cells were plated as described for the apoptosis studies. To determine whether ERK activity was involved in a nonapoptotic response, cells were exposed to the same treatments described above for 12 h in the presence or absence of 50 µmol/L mitogen-activated protein kinase kinase (MEK)1 inhibitor (PD98059; New England Biolabs) (31). Apoptosis was assessed as described above using the Cell Death Detection ELISA plus system.
Transfection assays.
C3H10T cells were transiently transfected with either a calcium phosphate precipitation method as described (32) or with lipofectamine reagent according to the manufacturer’s instructions (Life Technologies). Cells were transfected with 2.5 µg pCEP4, 2.5 µg pCEP4c > s, 3.0 µg pcDNA3S/J or no plasmid (mock transfection).
Statistical analysis.
Data were analyzed by one-way ANOVA followed by Duncan’s Multiple Range test ( = 0.05) using SAS software (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Consistent with our previous results (10), ceramide treatment of C3H10T cells does not induce apoptosis (Fig. 1). A 10 µmol/L concentration of ceramide was used in all studies presented, but higher concentrations of ceramide, 50 µmol/L, were also used without induction of apoptosis (data not shown). On the other hand, a 10 µmol/L dose of ceramine, the nonmetabolizable analog of ceramide, induced a sevenfold increase in apoptosis compared with vehicle control (Fig. 1). Morphological changes with ceramine treatment, such as cell rounding and detachment, were apparent by 6 h post-treatment (data not shown). These data are consistent with our previous results using flow cytometry to demonstrate that 20 µmol/L ceramine results in 74% cell death at 24 h in C3H10T cells (10). However, cotreatment of ceramine and S1P did not result in an apoptotic response, showing that S1P protects the cells from ceramine-induced apoptosis (Fig. 1).
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To determine whether SAPK/JNK plays a role in the apoptotic response in C3H10T cells, SAPK/JNK activity was measured after sphingolipid treatment. Vehicle treatment from 2 to 8 h did not alter SAPK/JNK activation from time 0, with values of phosphorylated SAPK/total SAPK ranging from 0.74 ± 0.17 (2 h) to 0.96 ± 0.16 (8 h) compared with the value at time 0 of 0.78 ± 0.25 (data not shown). S1P treatment alone did not increase SAPK/JNK activity (Fig. 2B). However, both ceramine and ceramine plus S1P treatment increased SAPK/JNK activity compared with vehicle control (Fig. 2B).
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Because the combination treatment of C3H10T cells with ceramine and S1P increased both SAPK/JNK and ERK activities, yet did not induce apoptosis, the role of ERK activation in this nonapoptotic response was investigated by employing the MEK1 inhibitor (31) (PD98059; Fig. 5). Ceramine treatment increased the level of apoptosis over vehicle control in the absence or presence of the MEK1 inhibitor. The ceramine plus S1P treatment without the inhibitor (Fig. 5) did not cause an apoptotic response, similar to previous results (Fig. 1). However, cotreatment of ceramine plus S1P with the MEK1 inhibitor resulted in a greater apoptotic response than the vehicle control, demonstrating that ERK activation is essential for the protection of S1P against ceramine-induced apoptosis (Fig. 5).
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S1P was shown recently to be a high affinity and specific ligand for several members of the family of G-protein–coupled EDG receptors. To assess the role of the EDG receptors in mediating the action of S1P on inhibition of ceramine-induced apoptosis and on ERK activation, cells were pretreated with pertussis toxin (PTX), which interferes with G-protein–coupled receptor action, followed by treatment with the sphingolipids. Apoptosis in the PTX-treated cells was higher in the ceramine plus S1P–treated cells than in vehicle-treated controls, suggesting that the S1P actions are mediated, at least in part, through the G-protein–coupled EDG receptors (Fig. 6A). ERK activation was completely abolished by PTX treatment in the ceramine plus S1P–treated cells (Fig. 6B).
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Initially, the potential role of MKP-1 was explored by assessing the effect of S1P on the expression of MKP-1. S1P, only in combination with ceramine, increased the expression of MKP-1 with a peak at 6 h (3.63 ± 0.30-fold compared with vehicle control, P < 0.05, data not shown). To determine the role of MKP-1 in the inhibition of apoptosis by S1P in the ceramine plus S1P group, cells were transfected with a dn MKP-1 mutant gene. The dn MKP-1 mutant binds to its substrate, an activated MAPK, and forms a complex, but it cannot dephosphorylate the MAPK (20). Ceramine treatment in cells transfected with the dn MKP-1 mutant plasmid, the empty plasmid and mock-transfected cells all resulted in an apoptotic response as assessed by both the TUNEL assay and Cell Death Detection ELISA (Fig. 7). However, apoptosis was greater in the ceramine plus S1P treatment in the C3H10T cells containing the dn MKP-1 mutant plasmid than in mock- and empty plasmid-transfected controls (Fig. 7).
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cells.
To determine whether MKP-1 down-regulated the SAPK/JNK pathway, cells were transfected with the dominant negative MKP-1 mutant gene (dn MKP-1) mutant plasmid, treated with the various sphingolipids, and ERK and SAPK/JNK activities determined. Both ceramine and ceramine plus S1P treatments increased SAPK/JNK significantly by 2 and 4 h, and the activity returned to near basal levels by 6 h (Fig. 2B). However, in the presence of the dn MKP-1 mutant, SAPK/JNK activity was increased with ceramine and ceramine plus S1P treatments, and this was sustained throughout the time course of the experiment. The pattern of ERK activation was similar in the absence (Fig. 4B) or presence of the dn MKP-1 mutant (Fig. 4C). Because SAPK/JNK activity remained elevated in the presence but not the absence of the dn MKP-1 mutant, MKP-1 may preferentially down-regulate SAPK/JNK in C3H10T cells. In fact, the SAPK/ERK ratio in ceramine plus S1P–treated cells, which were not undergoing apoptosis, was <1 at all time points and 0.45 by 8 h. In contrast, the SAPK/ERK ratio in ceramine plus S1P–treated cells in the presence of the dn MKP mutant, when the cells were undergoing apoptosis, was >1 at all time points and remained at 1.73 at 8 h. In this case the balance of SAPK/ERK was shifted toward SAPK, and the cells underwent apoptosis.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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cells. Our study is the first to demonstrate that S1P, in combination with an apoptotic stimulus, can up-regulate the expression of MKP-1 and that MKP-1 plays a role in the regulation of apoptosis by S1P. Due to the abundance of sphingolipids in the diet and the diverse cellular effects these lipids have, understanding their role in disease prevention is of great importance. For example, it has been demonstrated that dietary sphingolipids inhibit colon carcinogenesis in animal models (33–35); the major digestive product of sphingolipids is sphingosine, which can inhibit cell growth and induce cell death in human colon cancer cell lines (35). Thus, dietary intake of sphingolipids regulates carcinogenesis, and the metabolites of sphingolipids regulate the cellular processes that regulate growth and death.
Ceramide has been shown to induce apoptosis, at least in part, by the induction of the SAPK pathway (7,36–38). Our studies also demonstrate that ceramine, like ceramide, stimulates apoptosis via SAPK/JNK. This observation is consistent with our previous studies showing that conversion of ceramide to S1P is critical to C3H10T cell survival (10) and that ceramine is not metabolized through ceramidase.
A sustained increase in SAPK/JNK activity is associated with an apoptotic response, whereas a sustained increase in ERK activity is associated with proliferation and a survival response (16). The present studies demonstrate that apoptosis mediated by activation of SAPK/JNK was opposed by S1P activation of the ERK pathway via EDG receptor activation and down-regulation of SAPK/JNK by MKP-1. Thus, shifting the balance of SAPK/JNK to ERK, which occurs after S1P treatment in C3H10T cells, promotes cell survival.
S1P activates ERK in several (9,12), but not all cell-based assays (39,40). Our studies are consistent with earlier studies that demonstrated S1P activation of ERK, but only in combination with ceramine treatment. Ceramine may act to sensitize cells to S1P either as a ceramide analog to regulate signaling pathways, or by downstream apoptotic mechanisms.
MKP-1 is involved in a variety of responses promoted by external stimuli. Although MKP-1 can down-regulate all members of the MAPK family, its most commonly identified substrate is ERK (41,42). Similar to our results, MKP-1 has also been demonstrated to play an important role in preventing apoptosis in cells treated with TNF- and UV radiation (41,42). In those experiments, the expression of MKP-1 increased with TNF- and UV radiation treatment, which then specifically down-regulated SAPK/JNK activity, thus preventing apoptosis. Our studies demonstrate that MKP-1 plays a role in S1P inhibition of apoptosis. The increase in MKP-1 protein levels at 6 h coincided with the time point at which SAPK/JNK activity levels began to decline. In the presence of the dn MKP-1 mutant construct, SAPK/JNK activation remained significantly elevated up to 8 h with the ceramine plus S1P treatment compared with a decline in SAPK/JNK without the dn MKP-1 mutant (Fig. 2). Moreover, this sustained SAPK/JNK activation was sufficient to induce apoptosis in the ceramine plus S1P treatment, as shown by the results indicating higher levels of apoptosis in the presence of the dn MKP-1 mutant. Thus, these results suggest that when both ERK and SAPK/JNK are activated in C3H10T cells, MKP-1 preferentially down-regulates SAPK/JNK activation. Therefore, S1P prevents ceramine-induced apoptosis through MKP-1, which preferentially down-regulates the SAPK/JNK pathway.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CMF-PBS, calcium/magnesium-free PBS; dn MKP-1, dominant negative MKP-1 mutant gene; EDG, endothelial differentiation gene; ERK, extracellular regulated kinase; FBS, fetal bovine serum; MAPK, mitogen-activated protein kinase; MKP, mitogen-activated protein kinase phosphatase; MEK, mitogen-activated protein kinase kinase; PTX, pertussis toxin; SAPK/JNK, stress-activated protein kinase/c-Jun N-terminal kinase; S1P, sphingosine-1-phosphate; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.
Manuscript received 15 March 2003. Initial review completed 9 May 2003. Revision accepted 4 August 2003.
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