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Originally published In Press as doi:10.1194/jlr.M300342-JLR200 on February 1, 2004

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Journal of Lipid Research, Vol. 45, 667-673, April 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Induction of lysosomal phospholipase A2 through the retinoid X receptor in THP-1 cells

Akira Abe, Heather K. Poucher, Miki Hiraoka and James A. Shayman1

Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

Published, JLR Papers in Press, February 1, 2004. DOI 10.1194/jlr.M300342-JLR200

1 To whom correspondence should be addressed. e-mail: jshayman{at}umich.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
An acidic phospholipase A2 (LPLA2) was recently purified and cloned. THP-1 cells were used to characterize the gene induction of LPLA2. THP-1 cells were stimulated with several differentiation agents. The LPLA2 mRNA and activity increased in cells treated with phorbol ester but not with vitamin D3, interferon-{gamma}, or granulocyte macrophage colony-stimulating factor. All-trans-retinoic acid enhanced mRNA expression and enzyme activity in a dose- and time-dependent manner. The natural 9-cis and 13-cis isomers of retinoic acid enhanced transcription and activity. Two classes of nuclear receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR), mediate retinoic acid signaling. Specific RAR and RXR agonists were used to identify the nuclear receptor responsible for LPLA2 induction by retinoic acid. Treatment with the RAR agonist 4-[E-2-tetrahydro-5,5,8,8-tetra-methyl-2-naphthalenyl]1-propenyl benzoic acid (TTNPB) resulted in a small and statistically significant increase of the mRNA expression and activity of LPLA2. The RXR agonist methoprene acid worked as well as all-trans-retinoic acid at increasing both mRNA and enzyme activity. The methoprene acid and TTNPB effects were not synergistic. The peroxisome proliferator-activated receptor {gamma} agonists 15-deoxy-{Delta}12,14-prostaglandin J2 and troglitazone failed to induce LPLA2 activity and mRNA.

Thus, an RXR-dependent pathway controls LPLA2 gene activation by retinoic acid in THP-1 cells.

Supplementary key words retinoic acid • lysosome • phospholipase • phorbol ester


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 REFERENCES
 
Recently, while investigating short-chain ceramide metabolism in MDCK cells, a novel enzyme was discovered that catalyzes the esterification of the ceramide molecule at the C-1 carbon (1). The esterification results from the transfer of the acyl group at the sn-2 position of a glycerophospholipid such as phosphatidylcholine or phosphatidylethanolamine to ceramide. The enzyme has both transacylase and phospholipase A2 (PLA2) activities that are Ca2+-independent and favored under acidic conditions. The enzyme was subsequently purified from bovine brain (2). Based on the partial amino acid sequences obtained from the purified enzyme, the gene encoding the enzyme was cloned and the bovine, mouse, and human sequences were obtained (3). The enzyme is a water-soluble glycoprotein with a molecular mass of 45 kDa and consists of a single polypeptide chain. The enzyme has a pH optimum at 4.5. The cellular location of the enzyme is primarily lysosomal. Therefore, the enzyme was named lysosomal phospholipase A2 (LPLA2) (3). These data suggested that there is a new pathway for phospholipid and ceramide metabolism in lysosomes. However, the biological function of LPLA2 still remains unknown.

The LPLA2 gene was first reported in a study designed to identify lipid metabolism-related genes differentially expressed in foam cells. The foam cells were derived from PMA-treated THP-1 cells (4). THP-1 is a cell line derived from a patient with acute monocytic leukemia. These cells are of monocytic origin and are known to acquire increased phagocytic ability upon treatment with PMA. These cells can be stimulated and differentiated by a variety of agents, such as PMA, retinoic acid, vitamin D3, interferon-{gamma}, and granulocyte macrophage colony-stimulating factor (GM-CSF) (5–10). Thus, agonists other than PMA could affect LPLA2 gene expression in THP-1 cells. To better understand the biological function of LPLA2, a search was initiated for a cellular mechanism of LPLA2 gene expression using these agonists.

In this study, it is reported that all-trans-retinoic acid (ATRA) is able to induce LPLA2 mRNA and enzyme activity in THP-1 cells and that the induction is through a retinoid X receptor (RXR)-dependent pathway, which is independent of retinoic acid receptor (RAR) or peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 REFERENCES
 
Reagents
PMA, 8-bromo-cAMP, and ATRA were obtained from Sigma (St. Louis, MO). 9-Cis- and 13-cis-retinoic acids, 4-[E-2-tetrahydro-5,5,8,8-tetra-methyl-2-naphthalenyl]1-propenyl benzoic acid (TTNPB), methoprene acid, 15-deoxy-{Delta}12,14-prostaglandin J2 (PGJ2), and troglitazone were purchased from Biomol (Plymouth Meeting, PA). Vitamin D3 was from Calbiochem (La Jolla, CA), and interferon-{gamma} was from Roche Applied Science (Indianapolis, IN). GM-CSF was obtained from BD Biosciences (San Jose, CA).

LPLA2 induction study
One million THP-1 cells were seeded into a 10 cm-style dish containing 10 ml of RPMI 1640 medium supplemented with 10% fetal calf serum, 100 U/ml penicillin, 100 µg/ml streptomycin, 2 mM L-glutamine, 4.5 g/l D-glucose, 1 mM sodium pyruvate, and 55 µM 2-mercaptoethanol. The cells were maintained in an incubator with 5% CO2 at 37°C. In LPLA2 induction studies, 1,000,000 THP-1 cells were seeded into a 10 cm-style dish containing 10 ml of RPMI 1640 supplemented medium as described above and incubated for 24 h. Then, the cells were treated with or without stimulant as indicated in the figure legends.

RT-PCR
After the treatment, total RNA was prepared from the THP-1 cells using the RNeasy kit (Qiagen, Valencia, CA). Five micrograms of total RNA was used to synthesize cDNA with oligo(dT) using the Super Script First-Stand synthesis system (Invitrogen, Carlsbad, CA) in a total volume of 20 µl. One microliter of the cDNA mixture synthesized was used for PCR. The sequences of PCR primers were 5'-CCATGGAGAAGGCTGGGG-3' and 5'-CCAAAGTTGTCATGGATGACC-3' for sense and antisense, respectively, of GAPDH and 5'-GGGACTACCGCAAGTTCTT-3' and 5'-AGGTTCCAGAAGCACACGTTT-3' for sense and antisense, respectively, of LPLA2. The PCR amplifications of GAPDH and LPLA2 were performed separately using Taq polymerase. The samples were denatured at 94°C for 2 min followed by cycles of 94°C for 1 min, 60°C for 1 min, and 72°C for 1 min. The subsequent extension incubation was at 72°C for 5 min. To analyze PCR products semiquantitatively, 19–23 cycles were performed. Amplified products were separated by agarose gel (1.5%) electrophoresis, stained with ethidium bromide, and visualized under an ultraviolet transilluminator.

Transacylase activity in soluble fraction
The treated cells were washed twice with cold phosphate-buffered saline and once with cold 0.25 M sucrose, 10 mM Hepes (pH 7.4). The resultant cell pellet was dispersed in 0.25 M sucrose, 10 mM Hepes (pH 7.4) and disrupted five times for 10 s by a probe-type sonicator at 0°C. The suspension was centrifuged for 1 h at 100,000 g at 4°C. The resultant supernatant was passed through a 0.2 µm filter and used for the transacylase assay. N-Acetylsphingosine (NAS) was used as an acyl group acceptor. The reaction mixture consisted of 40 mM sodium citrate (pH 4.5), 10 µg/ml BSA, and 40 µM NAS incorporated into phospholipid liposomes [phosphatidylcholine/phosphatidylethanolamine/dicetyl phosphate/NAS (5:2:1:2 in molar ratio)] and enzyme fraction (7 µg) in a total volume of 500 µl. The reaction was initiated by adding the enzyme fraction, kept for 30, 60, or 120 min at 37°C, and terminated by adding 3 ml of chloroform-methanol (2:1) plus 0.3 ml of 0.9% (w/v) NaCl. The mixture was centrifuged for 5 min at room temperature. The resultant lower layer was transferred into another glass tube and dried down under a stream of nitrogen gas. The dried lipid was dissolved in 40 µl of chloroform-methanol (2:1), half of which was applied on an HPTLC plate and developed in a solvent system consisting of chloroform-acetic acid (9:1). The plated was dried down and soaked in 8% (w/v) CuSO4, 5H2O, 6.8% (v/v) H3PO4, and 32% (v/v) methanol. The plate was briefly dried with a hair dryer and charred for 15 min in a 150°C oven. The plate was scanned, and the product content (1-O-acyl-N-acetylsphingosine) was measured with NIH Image 1.62 software. The data were compared between experimental groups as the specific activity of the transacylase (micrograms of 1-O-acyl-N-acetylsphingosine per minute per milligram of protein), and statistical significance was determined by a paired Student's t-test.


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
REFERENCES
 
Effects of agonists on LPLA2 induction in THP-1 cells
In a preliminary study, THP-1 cells were treated with different agonists for 3 days. During the treatment period, PMA-treated THP-1 cells became adherent to the plastic surface of the culture dish and developed a macrophage-like appearance, but ATRA-, interferon-{gamma}-, and GM-CSF-treated cells remained as aggregated, floating cells. Although half of the vitamin D3-treated THP-1 cells became adherent, they did not acquire a macrophage shape. After the treatment period, LPLA2 and GAPDH mRNAs were detected by RT-PCR, and the enzyme activity in the soluble fraction was determined by its transacylase activity. As expected, both LPLA2 messenger level and enzyme activity were increased in the PMA-treated cells (Fig. 1) . However, vitamin D3, interferon-{gamma}, and GM-CSF did not have any significant effect on LPLA2 gene expression. Interestingly, ATRA was able to induce both the LPLA2 mRNA and enzyme activity.



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  		Fig. 1. Effect of PMA (TPA), all-trans-retinoic acid (ATRA), vitamin D3 (VD3), interferon-{gamma}, or granulocyte macrophage colony-stimulating factor (GM-CSF) on lysosomal phospholipase A2 (LPLA2) expression in THP-1 cells. One million THP-1 cells were seeded and treated with or without 10 nM PMA, 10 µM ATRA, 100 nM vitamin D3, 100 U/ml interferon-{gamma}, or 100 pg/ml GM-CSF for 3 days. After treatment, RT-PCR amplification of total RNA extracted from the treated cells was carried out and the 1-O-acylceramide synthase activity of the soluble fraction obtained from the treated cells was determined as described in Materials and Methods. The transacylase activity (ACS) values represent means ± SD of three independent measurements. The specific activities and P values of the agonist-stimulated groups versus the control group were as follows: control, 0.254 ± 0.008; PMA, 2.249 ± 0.160 (7.72 x 10-5); ATRA, 0.554 ± 0.030 (2.72 x 10-5); vitamin D3, 0.198 ± 0.045 (0.01); INF-{gamma}, 0.209 ± 0.023 (0.031); and GM-CSF, 0.301 ± 0.055 (0.222). NAS, N-acetylsphingosine.

 
Although LPLA2 has some possible phosphorylation sites, intracellular LPLA2 is localized to the lysosomal lumen. Therefore, LPLA2 should not be available as a substrate for the wide variety of cytosolic kinases that regulate many enzyme activities and intracellular signals. As previously reported, the sugar moieties of the glycosylation sites of LPLA2 do not have any effect on the enzyme activity (3). Other posttranslational modification sites of LPLA2 that may affect enzyme activity were not found during analysis of the primary sequence. Therefore, an enhancement of LPLA2 activity in PMA- and ATRA-treated THP-1 cells is thought to be attributable to an increase in LPLA2 protein levels.

LPLA2 induction by retinoic acids in THP-1 cells
ATRA is known to activate retinoic acid response genes (11). Also, retinoic acid induces the differentiation of many types of cells, including THP-1 cells (5–7, 9). We next focused on LPLA2 induction by retinoic acid in THP-1 cells.

LPLA2 mRNA and activity were induced in a concentration-dependent manner (Fig. 2A) . THP-1 cells were then treated with 10 µM ATRA for 1, 3, and 5 days. Both LPLA2 mRNA and activity were increased in a time-dependent manner (Fig. 2B). To understand the mechanism underlying the enhancement of LPLA2 mRNA and activity levels by ATRA, THP-1 cells were treated with 10 µM ATRA for 4 days and then exposed to 1 µg/ml actinomycin D, a potent inhibitor of RNA polymerase II. LPLA2 mRNA levels were significantly higher in the ATRA-treated cells (Fig. 2C). When cells were incubated with actinomycin D for 1, 3, and 6 h, a significant reduction in LPLA2 mRNA was observed at 1 and 3 h after treatment in both ATRA-treated and untreated cells. The relative reduction was slightly greater in ATRA-treated cells compared with cells not exposed to ATRA. Thus, the increase in LPLA2 mRNA observed in the presence of ATRA was not attributable to an increase in mRNA stability. By 6 h, the mRNA levels were less than 10% of those observed in the absence of actinomycin D (Fig. 2D).





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  		Fig. 2. ATRA induces LPLA2 expression in a dose- and time-dependent manner in THP-1 cells. One million THP-1 cells were seeded and treated with different concentrations of ATRA for 3 days (A) or with 10 µM ATRA for the indicated times (B). After treatment, LPLA2 messenger level and LPLA2 activity in the treated cells were measured as described in Materials and Methods. The ACS values represent means ± SD of three independent measurements. For studies of mRNA stability (C and D), 1,000,000 THP-1 cells were seeded and treated with or without 10 µM ATRA for 4 days and then exposed to actinomycin D for 0, 1, 3, and 6 h. The relative mRNA levels of LPLA2 were defined as follows: relative mRNA level (%) = 100 x (band intensity of LPLA2 mRNA of actinomycin D-treated cells)/(band intensity of LPLA2 mRNA of untreated cells). The mRNA bands were scanned and quantified by NIH Image 1.62 software. The closed and open circles represent ATRA-treated and ATRA-untreated cells, respectively. In B, the specific activities and P values of the ATRA-stimulated cells versus the control group were as follows: control, 0.283 ± 0.041; 0.1 µM, 0.371 ± 0.027 (0.036); 1.0 µM, 0.479 ± 0.066 (0.012); 10 µM, 0.542 ± 0.042 (0.002).

 
There are several natural retinoic acid isomers that display biological activity in a number of cell lines and tissues (12). THP-1 cells were treated with 10 µM ATRA, 9-cis-retinoic acid, or 13-cis-retinoic acid for 3 days. 9-Cis- and 13-cis-retinoic acids showed the same effect as ATRA on LPLA2 induction (Fig. 3) . These retinoic acids can be interconvertible within the cell (13–15).



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  		Fig. 3. Effect of retinoic acid isomers on LPLA2 induction in THP-1 cells. One million THP-1 cells were seeded and treated in the presence of 10 µM ATRA, 10 µM 9-cis-retinoic acid, or 10 µM 13-cis-retinoic acid for 3 days. After treatment, LPLA2 messenger level and LPLA2 activity in the treated cells were measured as described in Materials and Methods. The ACS values represent means ± SD of three independent measurements. The specific activities and P values of the agonist-stimulated groups versus the control group were as follows: control, 0.245 ± 0.022; ATRA, 0.522 ± 0.020 (0.0001); 9-cis-retinoic acid, 0.548 ± 0.067 (0.002); 13-cis-retinoic acid, 0.545 ± 0.008 (2.36 x 10-5).

 
Effect of TTNPB or methoprene acid on LPLA2 induction in THP-1 cells
There are two types of nuclear receptors involved in retinoic acid signaling. One is the RAR that binds ATRA and 9-cis-retinoic acid (16, 17). The other is the RXR that binds 9-cis-retinoic acid specifically (18–20). Ligand binding results in the activation of each receptor. The activated receptor monomer forms a homodimer or a heterodimer with another activated nuclear receptor and then activates a target gene (21). To identify the nuclear receptor that responds to LPLA2 induction by retinoic acid in THP-1 cells, RAR and RXR agonists were used.

TTNPB was used as an RAR agonist (22), and methoprene acid was used as an RXR agonist (23). THP-1 cells were treated with TTNPB and/or methoprene acid for 3 days. TTNPB treatment resulted in a slight increase of the mRNA expression and activity of LPLA2 (Fig. 4) . By contrast, the RXR agonist methoprene acid enhanced LPLA2 gene expression, as did ATRA (Fig. 4). However, methoprene acid did not work with TTNPB additively or synergistically, suggesting that the formation of an RAR-RXR dimer is not related to the upregulation of LPLA2 gene expression by retinoic acid in THP-1 cells. These results indicate that RXR is primarily involved in LPLA2 gene activation by retinoic acid in THP-1 cells and also suggest that 9-cis-retinoic acid converted from other retinoic acids in the THP-1 cells acts as an active ligand in LPLA2 gene activation by retinoic acid.



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  		Fig. 4. Effect of retinoic acid receptor or retinoid X receptor (RXR) agonist on LPLA2 induction in THP-1 cells. One million THP-1 cells were seeded and treated in the presence of 10 µM ATRA, 10 µM 4-[E-2-tetrahydro-5,5,8,8-tetra-methyl-2-naphthalenyl]1-propenyl benzoic acid (TTNPB), 100 µM methoprene acid, or 10 µM TTNPB plus 100 µM methoprene acid for 3 days. After treatment, LPLA2 messenger level and LPLA2 activity in the treated cells were measured as described in Materials and Methods. The ACS values represent means ± SD of three independent measurements. The specific activities and P values of the agonist-treated groups versus the control group were as follows: control, 0.219 ± 0.020; ATRA, 0.541 ± 0.024 (5.46 x 10-5); methoprene acid, 0.516 ± 0.066 (0.0017); TTNPB, 0.341 ± 0.016 (0.011); TTNPB plus methoprene acid, 0.561 ± 0.008 (9.89 x 10-6).

 
Effect of RXR or PPAR{gamma} agonists on LPLA2 expression in THP-1 cells
Recently, RXR was found to form a heterodimer with PPAR{gamma}, which is one of the lipid-sensing nuclear receptors (24). The possibility that PPAR{gamma} is involved in LPLA2 gene activation by retinoic acid was next considered. In this study, PGJ2 and troglitazone were used as PPAR{gamma} agonists (25–28). The cells were treated for 3 days with these agents. Neither PGJ2 nor troglitazone significantly enhanced LPLA2 gene expression (Fig. 5) . Also, these ligands did not work additively or synergistically with methoprene acid to increase LPLA2 expression. These results indicate that LPLA2 gene activation by retinoic acid in THP-1 cells is independent of PPAR{gamma}.



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  		Fig. 5. Effect of peroxisome proliferator-activated receptor {gamma} agonist on LPLA2 induction by RXR agonist in THP-1 cells. One million THP-1 cells were seeded and treated in the presence of 10 µM ATRA, 100 µM methoprene acid, 3 µM 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2), 15 µM troglitazone, 100 µM methoprene acid plus 3 µM PGJ2, or 100 µM methoprene acid plus 15 µM troglitazone for 3 days. After treatment, LPLA2 messenger level and LPLA2 activity in the treated cells were measured as described in Materials and Methods. The ACS values represent means ± SD of three independent measurements. The specific activities and P values of the agonist-treated groups versus the control group were as follows: control, 0.225 ± 0.006; ATRA, 0.479 ± 0.043 (0.0005); methoprene acid, 0.442 ± 0.043 (0.009); 15d-PGJ2, 0.215 ± 0.009 (0.039); troglitazone, 0.280 ± 0.061 (0.196); methoprene acid plus PGJ2, 0.465 ± 0.040 (0.0005); methoprene acid plus troglitazone, 0.490 ± 0.085 (0.006).

 
The effect of PMA or cAMP on LPLA2 induction via RXR in THP-1 cells
Phorbol myristate acetate is able to activate LPLA2 gene induction to a greater degree than ATRA, suggesting the possibility that PMA augments the induction pathway of LPLA2 by retinoic acid (Fig. 1). Therefore, THP-1 cells were treated with methoprene acid and/or phorbol ester for 3 days. The increase of enzyme activity in the cells treated with both agonists was additive (Fig. 6A) . cAMP is known to enhance the expression of some genes synergistically with ATRA (5, 29, 30).The cell-permeable cAMP analog, 8-bromo-cAMP, did not have any effect on LPLA2 induction in the presence or absence of ATRA in THP-1 cells (Fig. 6B). These results suggest that the upregulation of LPLA2 gene expression by ATRA is independent of a protein kinase C (PKC)- or PKA-related pathway.




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  		Fig. 6. Effect of PMA or 8-bromo-cAMP (8-Br-cAMP) on LPLA2 induction by RXR agonist or ATRA in THP-1 cells. One million THP-1 cells were seeded and treated in the presence of 100 µM methoprene acid, 10 nM PMA, or 100 µM methoprene acid plus 10 nM PMA for 3 days (A) or 10 µM ATRA, 1 mM 8-bromo-cAMP, or 10 µM ATRA plus 1 mM 8-bromo-cAMP for 3 days (B). After treatment, LPLA2 activity or LPLA2 messenger level in the treated cells was measured as described in Materials and Methods. The ACS values represent means ± SD of three independent measurements. For panel A, the specific activities and P values of the agonist-treated groups versus the control group were as follows: control, 0.267 ± 0.014; methoprene acid, 0.443 ± 0.067 (4.28 x 10-5); PMA, 0.843 ± 0.089 (0.004); methoprene acid plus PMA, 0.988 ± 0.043 (1.06 x 10-5).

 
In summary, three primary observations resulted from this study. First, the transcriptional expression and enzyme activity of LPLA2 is increased as a function of its concentration and time after ATRA exposure. These changes do not appear to be the result of an increase in mRNA stability. Second, the upregulation of LPLA2 gene expression by retinoic acid in THP-1 cells is primarily attained via an RXR-dependent pathway, which is independent of RAR or PPAR{gamma}. Third, the RXR-dependent pathway is not affected by the PKA or PKC pathway.

These results are consistent with a direct role for RXR in the transcriptional regulation of LPLA2. However, the time course for the increase in LPLA2 mRNA in response to ATRA and the RXR agonist is prolonged, lasting several days. Thus, more global, retinoid-dependent changes in THP-1 cells may be contributing to the increases in mRNA and enzyme activities. Future studies on the LPLA2 promotor will be required to delineate this possibility.

THP-1 cells differentiate and acquire macrophage-like properties and phagocytose foreign substances such as cell fragments, microorganisms, and lipoproteins. The substances ingested into the cell are sorted within an endosome or phagosome by receptor- or nonreceptor-mediated endocytosis (31–34). The endosome or phagosome fuses with a lysosome that contains a variety of hydrolases. As a result, the foreign substances are degraded. Retinoic acid may stimulate the degradation or turnover of such foreign substances containing phospholipids in phagocytic THP-1 cells.

The observed upregulation of LPLA2 gene expression by retinoic acid may be a cell- or tissue-specific event because retinoic acid has failed to induce LPLA2 gene expression in COS-7, MDCK, or T293 cells (our unpublished data). A better understanding of the molecular mechanisms of LPLA2 gene expression by retinoic acid will require the study of the retinoic acid response elements regulating the LPLA2 gene.

Manuscript received August 4, 2003 and in revised form November 21, 2003.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
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