Published online before print April 6, 2006, doi: 10.1161/01.ATV.0000220383.19192.55
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Transforming Growth Factor-ß–Induced Expression of the Apolipoprotein E Gene Requires c-Jun N-Terminal Kinase, p38 Kinase, and Casein Kinase 2
From the Cardiff School of Biosciences, Cardiff University, United Kingdom.
Correspondence to Dipak P. Ramji, Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. E-mail Ramji{at}cardiff.ac.uk
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Abstract |
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Objective— The cytokine transforming growth factor-ß (TGF-ß) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-ß have not been characterized and were therefore investigated.
Methods and Results— Using THP-1 cell line as a model system, with key findings confirmed in primary cultures, we show that TGF-ß induces the expression of apoE, and this is prevented by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase, and casein kinase 2 (CK2). In support for an important role for these pathways, TGF-ß activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-ß also increases the phosphorylation and expression of c-Jun, a downstream target for JNK action and a component of activator protein-1 (AP-1), and DN c-Jun inhibits the induction of apoE expression in response to the cytokine. AP-1 DNA binding was also induced by TGF-ß, and the action of p38 kinase, JNK, and CK2 converged on the activation of c-Jun/AP-1.
Conclusions— These studies reveal a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the TGF-ß–induced expression of apoE.
The mechanisms underlying the regulation of apolipoprotein E expression in monocytes/macrophages by the antiatherogenic cytokine TGF-ß were investigated. We show a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the response, which have implications to the development of atherosclerosis.
Key Words: apolipoprotein E • atherosclerosis • macrophage • TGF-ß • signal transduction • gene expression
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Introduction |
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Atherosclerosis, the leading cause of death in Westernized societies, is a form of chronic inflammation regulated by the action of cytokines.1 Among the cytokines, transforming growth factor-ß (TGF-ß) plays a potent antiatherogenic role.2 For example, TGF-ß inhibits foam cell formation3 and the production of NO,4 induces the expression of tissue inhibitors of metalloproteinases,5 and stimulates the expression of interleukin-1 receptor antagonist,6 all of which are largely antiatherogenic actions. The cytokine also acts in an anti-inflammatory manner as demonstrated by a profound inflammatory response in TGF-ß–deficient mice.7 In addition, inhibition of TGF-ß signaling accelerates the development of atherosclerosis in murine models of the disease.8 Furthermore, a number of studies have found an inverse association between TGF-ß levels and the development of atherosclerotic lesions.2,9
Because TGF-ß inhibits foam cell formation, it is essential that a detailed understanding is obtained of the action of the cytokine on the expression of key genes implicated in the process and the molecular mechanisms through which this is achieved. Such studies will improve our understanding of the molecular basis of foam cell formation and atherosclerosis and, in the longer term, lead to the identification of potentially novel targets for therapeutic intervention. TGF-ß inhibits the expression of lipoprotein lipase10 and scavenger receptors A and CD36,11–12 implicated in the uptake of cholesterol, and induces the expression of those involved in cholesterol efflux, such as ATP-binding cassette transporters A1 and G1.3,13
Apolipoprotein E (apoE), a major component of several classes of plasma lipoproteins, is a key stimulator of cellular cholesterol efflux and reverse cholesterol transport.14 The apoE expressed by monocytes/macrophages has potent antiatherogenic properties.14 Because of such antiatherogenic actions of apoE and TGF-ß, the present study was aimed at investigating the regulation of apoE expression in monocytes and macrophages by TGF-ß and to delineate the molecular mechanisms by which this is achieved.
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Methods |
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For details regarding cell culture and RT-PCR, please see the online Methods, available at http://atvb.ahajournals.org.
Materials
The human monocytic leukemia THP-1 cell line was from the European Collection of Animal Cell Cultures. The antisera were obtained from Biogenesis (apoE), Sigma (ß-actin), Santa Cruz Biotechnology (phospho–c-Jun [Ser63], c-Jun, and casein kinase 2 [CK2-
]), and Cell Signaling Technology (phospho-p38MAPK [Thr180/Tyr182], p38MAPK, phospho–c-Jun N-terminal kinase [JNK; Thr183/Tyr185], and JNK). Curcumin, Apigenin, SB202190, and SB203580 were from Merck Biosciences (Calbiochem), SP600125 was from Affiniti, cytokines from Peprotech, and the in vitro JNK kit from Cell Signaling Technology.
Preparation of Cell Extracts, SDS-PAGE, Western Blot Analysis, Immunoprecipitation of Proteins, and In Vitro Kinase Assays
Whole cell extracts were made in a buffer containing both phosphatase and protease inhibitors to maintain the proteins in an intact, phosphorylated state as described previously.15 SDS-PAGE and Western blot analysis were performed as described previously.10,15–16 Immunoprecipitation of proteins from cell extracts (100 to 150 µg) was performed using protein A/G-agarose beads as described previously.15 The immunoprecipitated protein was eluted from the agarose beads by addition of 50 µL of 0.1 mol/L glycine, pH 2.5, followed by incubation for 10 minutes at 4°C with gentle rotary mixing. The mixture was then centrifuged at 9000g for 2 minutes at 4°C, and the supernatant was subjected to SDS-PAGE and Western blot analysis as described previously.10,15–16 The nonradioactive JNK activity assay was performed using a kit from Cell Signaling Technology. The radioactive assay for CK2 was performed as described previously.15
Electrophoretic Mobility Shift Assay
The radiolabeling of oligonucleotides, preparation of whole cell extracts, and electrophoretic mobility shift assay (EMSA) was performed as previously described.10,15–16 The sequences of the oligonucleotides were 5'-GCTAGTGATGAGTCAGCCG-3' and 5'-GGATCCGGCTGACTCATCA-3' for consensus activator protein-1 (AP-1); 5'-GGGTTCAAGCGATTCTCCTGCCTCAGCCTCCC-AA-3' and 5'-GCTACTTGGGAGGCTGAGGCAGGAGAA-TCGCTTGA-3' for AP-1 element from the apoE gene promoter and 5'-GCCTTGGCATTA-3' and 5'-GCTAATGCCAAG-3' for nuclear factor-1 (NF-1).
Transfection of Cells
Transfection of THP-1 cells was performed using Fugene-6 as described by the manufacturer (Roche). The cells were incubated with the Fugene-6:DNA complex for 3 hours and then either left untreated or exposed to TGF-ß for 20 hours.
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Results |
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TGF-ß Induces ApoE Expression in Monocytes and Macrophages
Previous research on the action of TGF-ß on apoE has been restricted to a single, limited study in mouse peritoneal macrophages that showed that the cytokine induces its expression.17 Although apoE is expressed in monocytes, its regulation by TGF-ß has not yet been investigated and was therefore analyzed by RT-PCR on primary human monocytes. TGF-ß induced the expression of apoE mRNA but not the control 28SrRNA in these cells (supplemental Figure IA, available online at http://atvb.ahajournals.org).
The mechanism by which TGF-ß induces apoE expression was investigated next. Because primary monocytes/macrophages are difficult to transfect with exogenous DNA, the analysis was performed on THP-1 cells,18 which have been used extensively to investigate the regulation of genes in monocytes/macrophages implicated in atherogenesis, with demonstrated conservation of mechanisms with primary cultures. The action of TGF-ß on apoE expression in THP-1 monocytes and macrophages is not known and was therefore investigated first. Interferon-
(IFN-) was included in representative experiments for comparative purposes because this cytokine has been shown previously to inhibit apoE expression.14,19 Consistent with previous studies, IFN- decreased apoE mRNA expression in both monocytes and macrophages. In contrast, TGF-ß caused a marked increase in the expression of apoE mRNA but not that for the control gene (supplemental Figure IB). In the experiments on THP-1 macrophages, the cells were incubated simultaneously with PMA and cytokine. To rule out the possibility that the action of TGF-ß was attributable to the use of such an experimental approach, and to extend the studies to the expression of cellular and secreted apoE protein, THP-1 monocytes were first differentiated with PMA and then either left alone or incubated with TGF-ß. Cells that were incubated together with PMA and TGF-ß were also included along with THP-1 monocytes that were either left untreated or incubated with the cytokine. TGF-ß induced the expression of apoE mRNA along with the cellular and secreted protein in all the experimental conditions used (supplemental Figure IC and ID).
JNK and p38 Kinase Are Required for the TGF-ß–Mediated Induction of ApoE Expression
The signal transduction pathway(s) required for the TGF-ß–induced expression of apoE was next investigated. Because such studies on THP-1 macrophages could potentially be complicated by the presence of PMA, which is known to activate a number of signaling cascades,20 and because TGF-ß induces apoE expression in both monocytes and macrophages, we decided to focus the analysis on monocytes and then investigate whether key mechanisms also operate in macrophages. Further experiments showed that TGF-ß induces the expression of apoE in a concentration- dependent manner, with maximal increase of 
5-fold seen with 30 ng/mL of the cytokine (supplemental Figure IIA). In addition, TGF-ß induces the expression of apoE mRNA or protein by 3 to 6 hours, and this continues throughout the 24-hour incubation period (supplemental Figure IIB and IIC).
From a range of pharmacological inhibitors against components of different signal transduction pathways studied, the TGF-ß–mediated induction of apoE mRNA or protein expression was attenuated in a concentration-dependent manner by SB202190, an inhibitor of p38 kinase, and curcumin and SP600125, inhibitors of the JNK pathway (Figure 1A). To investigate whether the JNK and p38 kinase pathways are also required in macrophages, THP-1 cells were first differentiated with PMA and then incubated in the absence or the presence of TGF-ß without or with the JNK inhibitor curcumin or the p38 kinase inhibitor SP202190. In contrast to monocytes, both curcumin and SB202190 inhibited the differentiation-induced, TGF-ß–independent expression levels of apoE, but not the control 28SrRNA, in macrophages (supplemental Figure III). However, more important, both pharmacological agents also abolished the TGF-ß–induced expression of apoE in macrophages (supplemental Figure III). The concentration of all the inhibitors used in this study was based on an extensive literature survey of their actions in monocytes/macrophages. In addition, the action of all the pharmacological agents used was demonstrated not to be the result of any cytotoxicity as they had no effect on either the viability of the cells, as judged by the trypan blue exclusion assay (data not shown), or the expression levels of a constitutively expressed marker (eg, Figure 1).
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The experiments on the action of the inhibitors were so far restricted to THP-1 cells, and representative experiments were therefore performed on primary monocyte cultures. A lower concentration of the inhibitors (10 µmol/L) was used because primary cultures were found to be more sensitive to them compared with THP-1 cells. As shown in Figure 1B, the TGF-ß–mediated induction of apoE mRNA expression was prevented by the JNK inhibitor SP600125, and 2 inhibitors of p38 kinase (SB202190 and SB203580). Therefore, these studies suggest a potentially key role for the p38 kinase and JNK pathways in the action of TGF-ß on apoE expression, which was investigated in detail.
Activation of p38 kinase requires phosphorylation on threonine 180 and tyrosine 182. Time course Western blot analysis showed that incubation of THP-1 cells with TGF-ß led to a marked increase in the levels of dually phosphorylated, but not total, p38 kinase within 1 hour, and this continued to increase until 24 hours (data not shown). The effect of SB202190 and SB203580 on this TGF-ß–mediated activation of p38 kinase was investigated next. As shown in Figure 2A, TGF-ß increased the level of the dually phosphorylated, but not total, p38 kinase, and this was inhibited by both pharmacological agents.
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Activation of JNK requires phosphorylation at tyrosine 185 and threonine 183. Initial time course Western blot analysis showed that similar to p38 kinase, TGF-ß increased the levels of dually phosphorylated but not total p46 form of JNK within 1 hour, and this continued to increase until 12 hours and then remained relatively constant thereafter (data not shown). However, the signals for phospho-JNK from Western blot analysis were relatively weak, and the findings were therefore confirmed by immunoprecipitation experiments (Figure 2B). Such a TGF-ß–induced phosphorylation of JNK was also associated with an increase in the activity of the enzyme, as judged by its ability to phosphorylate its key downstream target c-Jun (a member of the AP-1 family of transcriptional regulators) in vitro (Figure 2C and 2D). As expected, the activity of JNK was inhibited by SP600125 and curcumin (Figure 2C and 2D).
The regulation of c-Jun is complex and can occur at the level of synthesis or activity, which is modulated by phosphorylation of serines 63 and 73.21 Therefore, we next investigated the action of TGF-ß on the levels of phospho–c-Jun and total c-Jun, with apoE being included for comparison. TGF-ß caused a dramatic increase in the levels of phospho–c-Jun, total c-Jun, and apoE, and these were all inhibited by SP600125 (Figure 2E), thereby indicating that the cytokine induces both the phosphorylation and the expression of c-Jun.
To confirm an important role for JNK, p38 kinase, and c-Jun further, the action of DNA constructs specifying for dominant-negative (DN) forms of these proteins22–24 on apoE mRNA expression was investigated. THP-1 cells were transfected with the pcDNA3 control vector or the DN plasmids using Fugene-6, which produces extremely high transfection efficiency, and incubated in the absence or the presence of TGF-ß. RT-PCR analysis showed that the TGF-ß–induced apoE mRNA expression was inhibited by DN forms of JNK, p38 kinase, and c-Jun (Figure 3).
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Having established that c-Jun is a key downstream target for TGF-ß action on apoE expression, we wondered whether the p38 kinase pathway also converges on this transcription factor. To investigate this possibility, the effect of SB202190 on the TGF-ß–induced expression of c-Jun was investigated, using SP600125 for comparison. Figure 4A shows that, similar to SP600125, SB202190 also inhibits the induction of c-Jun expression.
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3 independent experiments.
Because c-Jun is a major component of AP-121 and, as an AP-1–like recognition sequence in the promoter of the apoE gene, has been implicated in its induced expression during macrophage differentiation,25 EMSAs were also performed to evaluate the effect of TGF-ß and the inhibitors on DNA–protein interactions. As shown in Figure 4
B, 2 major DNA–protein complexes were seen with a consensus AP-1 recognition sequence. TGF-ß induced the binding of both factors, and this was inhibited by SB202190 and SP600125. The specificity of the DNA–protein interactions was confirmed by competition EMSA, in which competition was seen with an AP-1 but not the unrelated NF-1 binding site (Figure 4B). A similar action of TGF-ß and the inhibitors was also seen with the AP-1–like sequence from the apoE gene promoter (data not shown).
A Novel Role for CK2 in the TGF-ß–Induced Expression of ApoE
A potential role for CK2 in TGF-ß signaling has been suggested by 2 recent studies,26–27 although there is a discrepancy in the effect of the cytokine on the activity of the enzyme (inhibition in hepatocytes and stimulation in mesangial cells). We thus investigated the action of TGF-ß on CK2 in THP-1 cells and its potential role in the induction of apoE expression. Figure 5A shows that TGF-ß induces CK2 activity, and this is attenuated by the selective inhibitor apigenin.15,26 The TGF-ß–induced expression of apoE mRNA or protein was also inhibited in a concentration-dependent manner by apigenin (Figure 5B and 5C). Consistent with this finding, expression of DN CK228 inhibited the stimulation of apoE expression in the presence of TGF-ß (Figure 5D). As the action of JNK and p38 kinase converged on AP-1, we wondered whether this was also the case for CK2. As shown in Figure 5E, the TGF-ß–induced binding of AP-1 was also inhibited by apigenin. These results implicate a potentially novel role for CK2 in the regulation of apoE expression.
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Discussion |
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Consistent with a potent antiatherogenic role for TGF-ß, we show here that the cytokine induces the expression of apoE in both monocytes and macrophages (supplemental Figure I). Such an action also correlates well with previous studies showing that the cytokine inhibits foam cell formation and suppresses the expression of a number of genes implicated in the uptake of lipoproteins and simultaneously induces the expression of those involved in stimulating cholesterol efflux.3,11–13 The mechanisms underlying the TGF-ß–induced expression of such genes remain unclear. We show for the first time a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the activation of apoE expression.
Transcriptional regulation of the apoE gene is extremely complex, with enhancer sequences up to 30 kb being required in addition to the proximal promoter region.14 Although actinomycin D, an inhibitor of RNA–polymerase II-mediated gene transcription, prevented the TGF-ß–mediated induction of apoE mRNA expression, thereby indicating a major role for transcriptional regulation, the cytokine failed to increase reporter gene activity when transient transfection assays were performed with the apoE proximal promoter-luciferase reporter gene construct by itself or containing the ME.1 or ME.2 enhancer elements that have been implicated in the macrophage-specific expression of the gene in transgenic mice.14 This may be because of the requirement of apoE regulatory sequences outside those present in the DNA constructs used or a specific chromatin context in the cells that is absent in the transfected plasmids. Bioinformatic analysis of the apoE promoter and enhancer sequences shows a number of consensus AP-1 binding sites. Interestingly, one of these sites in the proximal promoter region (position –602) has already been shown to be important for the induction of apoE expression during PMA-induced differentiation of THP-1 monocytes into macrophages.25 Indeed, TGF-ß induces the binding of AP-1, and this was affected by inhibitors of p38 kinase, JNK, and CK2 (Figures 4 and 5). Interestingly, when the action of curcumin and SB202190 on apoE expression in macrophages was investigated, inhibition was seen of both the TGF-ß–independent expression, driven by the differentiating agent PMA, and that induced by this cytokine (supplemental Figure III). AP-1 site(s) have been found to play an important role in the regulation of a subset of TGF-ß response genes, including most of the extracellular matrix genes that play a key role in the pathogenesis of atherosclerosis.1–2 It is interesting to note that the expression of a large number of such genes is also induced by PMA through AP-1–like sequences.29
The role of the Smad proteins in TGF-ß signaling is well established.30 However, a widespread involvement of additional pathways in the action of TGF-ß are increasingly being identified.30 Our studies identify a potentially novel role for the p38 kinase, CK2, and JNK pathways in the action of TGF-ß in monocytes and macrophages. TGF-ß induced a sustained activation of p38 kinase, CK2, and JNK. Although the activation of these enzymes in most cases is transient, such sustained activation has been seen previously.31 Similarly, although c-Jun is an immediate early gene, its delayed or prolonged activation/expression has also been reported previously.32
In conclusion, we identified the signaling pathways underlying the TGF-ß–induced expression of apoE in monocytes and macrophages, which should potentially play a key role in the regulation of foam cell formation during atherosclerosis, given this cytokine stimulates cholesterol efflux and apoE is a major regulator of this process. Future studies should seek to delineate the mechanism by which the different components converge on c-Jun and the role of the pathway in the TGF-ß–mediated regulation of other genes implicated in foam cell formation and atherosclerosis.
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Acknowledgments |
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We thank the British Heart Foundation for financial support.
Received December 6, 2005; accepted March 23, 2006.
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