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-induced ATF3 expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells
1 Department of Functional Genomics, Medical Research Institute, and 2 Laboratory of Gene Expression, School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Janpan
3 Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Abstract |
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(tumour necrosis factor )-induced ATF3 expression in vascular endothelial cells. In human umbilical vein endothelial cells, the expression of constitutively active MKK7 (MAPK kinase 7) increased the number of ATF3-positive cells, and dominant negative MKK7 suppressed the TNF-induced expression of ATF3, indicating a requirement for the JNK pathway. In contrast, the expression of constitutively active or dominant negative MEK1/2 (MAPK/ERK kinase 1/2) suppressed or enhanced TNF-mediated induction of ATF3, respectively. In support of this, the MEK1/2 specific inhibitor U0126 enhanced the expression of ATF3 induced by TNF. Furthermore, the ERK pathway inhibits the TNF-mediated induction of ATF3 mRNA, but not its stability, suggesting the involvement of ERK activity in the transcriptional regulation of the ATF3 gene. Our results suggest that TNF-induced ATF3 gene expression is bidirectionally regulated by the JNK and ERK pathways in vascular endothelial cells. |
Introduction |
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In vascular endothelial cells, ATF3 is induced by pathogenic stimuli such as homocysteine, oxidized low density lipoprotein or TNF (tumour necrosis factor ) (Cai et al. 2000; Kawauchi et al. 2002; McCully 1996; Nawa et al. 2002). TNF is a potent cytokine which is predominantly produced in macrophages, and which elicits a broad spectrum of responses in a variety of cells and organisms. TNF is thought to be a key regulator of atherogenesis and thrombogenesis, as well as other irritants, in vascular endothelial cells (Barath et al. 1990; Hallenbeck 2002; Lusis 2000; van Hinsbergh et al. 1988). TNF binds to surface receptors and activates intracellular signalling pathways to initiate downstream responses including the activation of transcription factors (Baud & Karin 2001). NF-
B (Nuclear factor-B) is one of the major transcription factors activated by TNF, and TNF-induced NF-B activation increases the expression of many genes that protect cells from apoptosis and participate in inflammatory and immune responses (de Martin et al. 2000). Another transcription factor, AP-1 (activator protein-1), is also implicated in pro-inflammatory responses and apoptosis following the activation of the MAPK (mitogen-activated protein kinase) signalling pathways (Baud & Karin 2001).
To date, four distinct classes of MAPKs have been identified, and include ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), p38 MAPK, and BMK1 (Big MAPK1)/ERK5 (Kyriakis & Avruch 2001; Lee et al. 1995). The ERK pathway is activated by a range of stimuli including growth factors, whereas the JNK, p38 MAPK and BMK1/ERK5 pathways are activated by pro-inflammatory cytokines and a variety of environmental stresses (Kyriakis & Avruch 2001). The JNK pathway also induces the expression of transcription factors including ATF3 (Cai et al. 2000; Yin et al. 1997). Here, we investigated the role of MAPK pathways in TNF-induced ATF3 expression in vascular endothelial cells, and found that the TNF-induced expression of ATF3 is bidirectionally regulated by the JNK and ERK pathways.
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Results |
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in HUVECs (human umbilical vein endothelial cells)
TNF is a multifunctional cytokine that plays a pivotal role in the inflammatory response of vascular endothelial cells, and modulates the expression of a wide variety of genes. To first investigate the effect of TNF on the induction of ATF3 in HUVECs, cells were either left untreated or treated with 20 ng/mL TNF for 15 min to 24 h. Whole cell lysates were then prepared for immunoblotting analysis of ATF3 expression. ATF3 expression was induced after 1 h of treatment with TNF, peaked at 8 h and subsequently declined. In contrast, the vehicle had no effect on ATF3 expression (Fig. 1A). We found that 8 h treatment with TNF (0–20 ng/mL) increased ATF3 expression in HUVECs in a dose-dependent manner, although the response was reduced at concentrations above 20 ng/mL (Fig. 1B).
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in various cell lines
In contrast to the HUVECs, Drysdale et al. (1996) showed that TNF did not induce ATF3 in the mouse macrophage cell line RAW 264.7. We therefore investigated whether TNF induces ATF3 expression in cell lines other than HUVECs. Immunoblotting analysis showed that under our conditions, TNF-induced ATF3 expression was detected in many of the cell lines examined, but not in all (Fig. 2A). The time course of ATF3 expression induced by TNF varied in the different cell lines. Immunofluorescence imaging of an anti-p65 antibody revealed that TNF caused nuclear accumulation of NF-B p65 in all cell lines, indicating that these cells are responsive to TNF (Fig. 2B and data not shown). The response of these cells to TNF was also confirmed using NF-B reporter gene analysis (data not shown).
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-induced ATF3 expression is negatively regulated by the ERK pathway
Since it has previously been established that TNF activates MAPK signalling pathways in various cell types, including HUVECs (Baud & Karin 2001; Westwick et al. 1994), we examined whether these pathways are activated under our conditions, by immunoblotting using phospho-specific antibodies. The results showed that the maximum level of JNK and p38 MAPK activity occurred after 15 min treatment with TNF, but was subsequently down-regulated after 30 min. The ERK pathway was activated in the absence of TNF and could not be further activated by TNF (Fig. 3A). The inclusion of serum contained in the medium induced ERK activity.
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-induced ATF3 expression. HUVECs were transfected with GST (glutathione S-transferase), the CA (constitutively active) form of MKK (MAPK kinase)7 (MKK7CA) or MKK6 (MKK6CA), which are major activators of the TNF-induced JNK and p38 MAPK pathways, respectively (Kyriakis & Avruch 2001). They were then immunostained for both endogenous ATF3 and transfected gene products. Immunofluorescence analysis showed that the proportion of ATF3-positive cells was greater in cells which over-expressed MKK7CA, compared to those that over-expressed the unrelated protein, GST (Fig. 3B,E). In contrast, MKK6CA did not affect ATF3 expression, whereas it increased dually phosphorylated p38 MAPK, implying that there was an activation of endogenous p38 MAPK (Fig. 3B,E). To determine whether TNF-induced ATF3 expression was suppressed by the DN (dominant negative) form of MKK, HUVECs were transfected with GST, MKK7DN or MKK6DN, and treated with TNF before immunostaining. Imunofluorescence analysis showed that the proportion of ATF3-positive cells was reduced in cells over-expressing MKK7DN, compared to those over-expressing GST. MKK6DN also had a small effect on TNF-induced ATF3 expression (Fig. 3C,E).
In HUVECs, by way of contrast, TNF-induced ATF3 expression was strongly attenuated by the over-expression of MEK1CA (constitutively active MAPK/ERK kinase 1), and enhanced by MEK1/2 DN (dominant negative MEK1/2) (Fig. 3D,E). These data suggest that the expression of ATF3 induced by TNF is up-regulated via the JNK pathway, but down-regulated via the ERK pathway.
Inhibition of ERK activity enhances the TNF-induced ATF3 expression
As the immunofluorescence analysis shown in Fig. 3 is not fully quantitative, we evaluated the effect of ERK activity on TNF-induced ATF3 expression by immunoblotting using an antibody for ATF3 after the treatment of HUVECs with TNF for the indicated times in either the absence or presence of the MEK1/2 specific inhibitor, U0126 (Favata et al. 1998). As indicated in Fig. 4A and B, U0126 enhanced the TNF-induced expression of ATF3 via inhibition of ERK activity, in good agreement with the results shown in Fig. 3D and E.
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(Fig. 4A, lower four panels). Similar results were obtained using another MEK1/2 specific inhibitor, PD98059 (Alessi et al. 1995) (Fig. 4C). Furthermore, reporter gene analysis indicated that the inhibition of ERK activity did not increase JNK activity (Fig. 4D). ATF3 expression was induced by TNF and enhanced with U0126 in HUVECs cultivated in a different medium (Fig. 4E). These findings demonstrate that the enhanced level of ATF3 expression with inhibiton of ERK is not attributable to the growing culture media. In the presence of U0126, ATF3 expression was induced at lower doses (0.002–0.02 ng/mL) of TNF (Fig. 4F), indicating that the suppression of ERK activity sensitizes HUVECs to TNF.
TNF-induced NF-B-dependent transcriptional activity in HUVECs is enhanced by suppression of the ERK pathway
ATF3 mRNA levels were measured following the treatment of HUVECs with TNF for 2 or 4 h in either the absence or presence of U0126. A Northern blot analysis showed that U0126 markedly increased the steady-state levels of ATF3 mRNA induced by TNF (Fig. 5A). Steady-state mRNA levels are generally dependent on transcription, the stability of mRNA, or both. The 3'-untranslated region of ATF3 mRNA contains AU-rich regions that are thought to destabilize mRNA (Chen & Shyu 1995), and MAPK signalling pathways are involved in mRNA stability (Chen et al. 1998; Winzen et al. 1999). To examine whether enhanced levels of ATF3 mRNA are derived from its stability, HUVECs were treated with TNF in the either presence or absence of U0126, and then incubated with the RNA transcription inhibitor, actinomycin D to remove the effects of newly synthesized mRNA. A Northern blotting analysis of the ATF3 mRNA levels showed that the rate of ATF3 mRNA degradation induced by TNF was not affected by U0126 (Fig. 5B,C). These findings indicate that the enhanced level of ATF3 mRNA in the presence of U0126 is due to transcriptional activation of the ATF3 gene, and suggest that the ERK pathway regulates the TNF-induced gene expression of ATF3.
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-mediated signalling also induces the activation of NF-B (de Martin et al. 2000), and potent NF-B binding sequences have been identified in the ATF3 promoter region (Liang et al. 1996). Therefore, to determine whether ATF3 is also regulated by TNF-induced NF-B activation, HUVECs, transfected with an NF-B-driven reporter plasmid, were treated for 24 h either with or without TNF. Reporter gene assays showed that the treatment of HUVECs with TNF resulted in an activation of NF-B (Fig. 5D). Recent studies have revealed that the ERK pathway regulates NF-B signalling in some cell lines containing THP-1 and T98G cells (Carter & Hunninghake 2000; Funakoshi et al. 2001). TNF-induced NF-B transcriptional activity was further enhanced in HUVECs by the MEK1/2 specific inhibitor U0126 (Fig. 5D). |
Discussion |
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initiates the induction of ATF3 in HUVECs, as was previously described (Kawauchi et al. 2002; Nawa et al. 2002). This induction was reduced when TNF concentrations exceeded 20 ng/mL. This reduction could be due to the cytotoxic effect of TNF, or such a strong stimulation might trigger signals that inhibit ATF3 expression. The contrasting results described above might be attributable to the expression levels of ATF3 if it is regulated in a stimuli-dependent manner. We further examined whether ATF3 was induced by TNF in other cell lines, as TNF does not induce ATF3 expression in the mouse macrophage cell line RAW 264.7 (Drysdale et al. 1996). We found that this induction was also observed in many cell lines, but not in all the cells examined, even though TNF-induced nuclear accumulation of NF-B p65 was observed in all cells. This indicates that the variation in the TNF-induced ATF3 expression is dependent on cell type.
TNF activates three distinct classes of the MAPK family (Baud & Karin 2001; Westwick et al. 1994). In HUVECs, we observed JNK and p38 MAPK activation by TNF, but in the presence of serum, the ERK pathway was activated in the absence of TNF. No further induction of the ERK pathway by TNF was detected under our conditions. Considering that TNF-induced ATF3 expression was enhanced by the MEK1/2 specific inhibitor U0126, the level of ERK activation may determine the sensitivity of cells to TNF.
ATF3 is induced either via the JNK (Cai et al. 2000; Yin et al. 1997) or the protein kinase A-dependent pathway (Chu et al. 1994). However, it has not been established whether other signalling pathways also regulate the induction of ATF3. In the present study, we have provided the first evidence that the ERK pathway is involved in the negative regulation of TNF-induced ATF3 expression, while the induction is likely to be mediated via the JNK pathway, as was previously described (Cai et al. 2000; Yin et al. 1997). As shown in Figs 3D and E, TNF does not affect ATF3 induction in HUVECs transfected with MEK1CA, suggesting that the enhanced ERK signals antagonize the TNF-mediated signalling pathway for ATF3 expression. We also observed a subtle effect of the p38 MAPK pathway on ATF3 expression compared with the JNK pathway. In preliminary data, we were able to show that the specific inhibitor of p38 MAPK, SB203580 (Lee et al. 1994; Whitmarsh et al. 1997), also reduced the ATF3 expression induced by TNF (data not shown). Further study is required to determine the involvement of p38 MAPK in ATF3 expression.
In addition, both BMK1/ERK5 (Lee et al. 1995) and its specific activator, MEK5 (Zhou et al. 1995), are activated by various stimuli, and are inhibited by the MEK1/2 specific inhibitors U0126 and PD98059 (Abe et al. 1996; Kamakura et al. 1999). However, we were unable to observe TNF-induced BMK1/ERK5 activation in HUVECs (data not shown), consistent with its lack of effect on vascular smooth muscle cells (Abe et al. 1996). These findings suggest that the BMK1/ERK5 pathway does not contribute to the ATF3 expression induced by TNF.
We have also provided evidence that the inhibition of ERK activity enhances TNF-induced expression of the ATF3 gene (Fig. 5A), suggesting that the elevated levels of ATF3 protein through ERK inhibition is, at least in part, attributed to the increased levels of ATF3 mRNA. Since ERK activity has no effect on the stability of ATF3 mRNA (Fig. 5B,C), we suggest that the ATF3 gene expression induced by TNF is negatively regulated at the transcriptional level via the ERK signalling pathway. Although we further examined ATF3 promoter activity using the well-established 1850 bp region of the 5'-flanking sequence of the ATF3 gene (Cai et al. 2000; Liang et al. 1996) on reporter analysis, it could not be induced by TNF in HUVECs or COS-7 cells under our conditions (data not shown). The 1850 bp promoter of ATF3 may lack the region required for the response to TNF, while some AP-1 and ATF/CRE binding sites exist in this promoter region (Liang et al. 1996).
ATF3 expression was enhanced with the inhibition of ERK when cells were incubated with low, near circulating, concentrations of TNF (Agnoletti et al. 1999; Levine et al. 1990). Considering that the stress arising from injuries activates ERK activity in vascular endothelium in vivo (Hu et al. 2000; Xu et al. 1996), the balance and timing of signals in the ERK and JNK pathways may regulate both the extent and time course of stress responses via the induction of ATF3 in vascular endothelial cells.
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Experimental procedures |
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The following antibodies and reagents were obtained from the indicated companies: TNFa (Calbiochem); MEK1/2 specific inhibitors, U0126 (Promega), PD98059 (Calbiochem); rabbit polyclonal antibodies for ATF3 and p65, and mouse monoclonal antibodies for Myc (9E10), ERK2, p38a MAPK and GST (Santa Cruz Biotechnology); mouse monoclonal antibody for HA (haemagglutinin) (12CA5) (Roche Diagnostics); rabbit polyclonal antibody for actin (Sigma); rabbit polyclonal antibodies for phospho ERK1/2, ERK1/2, phospho JNK, JNK, phospho p38 MAPK and p38 MAPK (New England Biolabs).
Expression plasmids
The ORF (open reading frame) of human MEK1 or MEK2 was amplified by PCR (polymerase chain reaction) using HeLa.S3 cDNA as a template. To construct the CA or DN form of MEK1, site-directed mutagenesis of Ser218 to Asp and Ser222 to Glu, or Ser218 and Ser222 to Ala was performed, respectively, using wild-type MEK1 as a template (Adachi et al. 1999). Likewise, site-directed mutagenesis of Ser222 and Ser226 in MEK2, which correspond to the mutated sites of the DN form of MEK1 into Ala was performed to construct the DN form of MEK2 (MEK2DN). Each mutated XhoI–NotI fragment was subcloned into a pME-Myc vector (Kamimoto et al. 2001), yielding pME-Myc-MEK1CA, pME-Myc-MEK1DN and pME-Myc-MEK2DN. Similarly, mouse MKK7g2 was amplified by PCR and site-directed mutagenesis of Ser287 and Thr291 to Asp, or Lys165 to Arg was performed to construct the CA or DN form of MKK7, respectively (Wang et al. 1998; Yamauchi et al. 1999). To construct the CA or DN form of MKK6, the site-directed mutagenesis of Ser207 and Thr211 to Glu, or Lys82 to Ala was performed, respectively, using human wild-type MKK6 as a template (Moriguchi et al. 1996; Raingeaud et al. 1996). The mutated SalI–NotI fragments were subcloned into a pME-HA vector (Moriguchi et al. 1996), yielding pME-HA-MKK7CA, pME-HA-MKK7DN, pME-HA-MKK6CA and pME-HA-MKK6DN. The nucleotide sequences were verified by DNA sequencing.
Cell culture and transfection
Primary cultures of HUVECs were purchased from Clonetics. Cells were grown in EBM-2 medium supplemented with 2% FBS (foetal bovine serum) and the other bullet kit additives in accordance with the manufacturer's protocol (Clonetics). Only in Fig. 4E, the cells were grown in medium 199 (Sigma) supplemented with 60 mg/mL endothelial cell growth substance (Sigma), 100 mg/mL heparin (Sigma), 20% FBS and antibiotics (1% penicillin-streptomycin; Life Technologies). Subconfluent cultures were passaged according to a standard trypsinization protocol. All experiments used HUVECs between passages three and eight. HeLa.S3 cells were cultured in MEM (minimum essential medium; Sigma) supplemented with 10% CS (calf serum) and antibiotics. MCF-7 cells were cultured in DMEM (Dulbecco's Modified Eagle's medium; Sigma) supplemented with 10% FBS, 1% NEAA (nonessential amino acids solution; Life Technologies) and antibiotics. 293, CV-1 and COS-7 cells were cultured in DMEM supplemented with 10% FBS and antibiotics. MG-63, MDCK and Mv.1.Lu cells were cultured in MEM supplemented with 10% FBS, 1% NEAA and antibiotics. NIH3T3 and BALB/3T3 cells were cultured in DMEM supplemented with 10% CS and antibiotics. NRK cells were cultured in MEM supplemented with 10% FBS and antibiotics. PC12 cells were cultured in DMEM/F12 (Sigma) 1 : 1 supplemented with 10% FBS and antibiotics. For the transfection assays, HUVECs were transfected with the appropriate combinations of expression plasmids using SuperFect (Qiagen) in accordance with the manufacturer's instructions.
Immunoblotting
Cells were lysed directly in 1 ¥ Laemmli sample buffer containing dithiothreitol, collected and then boiled. The aliquots were resolved by SDS (sodium dodecyl sulphate)-polyacrylamide gel electrophoresis, followed by electrotransfer to polyvinylidene difluoride membranes. For visualization, the blots were probed with the appropriate primary antibodies and detected with horseradish peroxidase-conjugated secondary antibodies (New England BioLabs and Bio-Rad) and an ECL kit (Amersham Pharmacia Biotech).
Immunofluorescence staining
Cells were fixed in 4% paraformaldehyde in PBS (phosphate-buffered saline), followed by permeabilization in PBS containing 0.2% Triton X-100. The cells were first incubated with primary antibodies, and then with the fluorescent-conjugated secondary antibodies. For the DNA staining, coverslips were incubated with Hoechst33258 (Sigma). Fluorescent images were analysed using an LSM510 confocal microscope (Zeiss).
RNA extraction and Northern blot analysis
For the RNA analysis, the cells were treated, and total RNA was extracted with Isogen (Nippon Gene) in accordance with the manufacturer's protocol. Total RNA (5 mg) was denatured, and the RNA was separated on a 1% agarose gel by electrophoresis. RNA was blotted overnight on to a Hybond-N+ nylon membrane (Amersham Life Science) by capillary action in a buffer containing 20 ¥ SSC (1 ¥ SSC is 150 mM NaCl plus 15 mM sodium citrate). RNA was fixed on the membrane by baking at 80 C for 2 h, and then hybridized to radiolabelled cDNA probes of human ATF3 at 42 C overnight in the hybridization mixture (6 ¥ SSC, 50% formamide, 1% SDS, 1 ¥ Denhardt's solution, 10% dextran sulphate and 100 mg/mL of denatured salmon sperm DNA). Full-length ATF3 cDNA was obtained from pCG-ATF3 plasmid (a gift from Dr T. Hai, Ohio State University) by PCR. Fifty ng of gel-purified cDNA was radiolabelled with a random priming kit (Takara) and [a-32P]deoxycytidine triphosphate (NEN), and were used as a probe. The membranes were washed twice at 55 C with washing buffer (0.1 ¥ SSC, 0.1% SDS), and the hybridized transcripts were visualized using a BAS2000 image analyser (Fuji Film).
Messenger RNA stability assay
Cells were treated with TNFa in either the absence or presence of 10 mM U0126. After 4 h, actinomycin D was added to a final concentration of 10 mg/mL. At various times after the addition of actinomycin D, total RNA was isolated and 5 mg of each sample underwent a Northern blotting analysis as described above. Autoradiographic signals were visualized, quantified by laser densitometry and normalized to 28S ribosomal RNA signals.
Reporter gene assays
1.5 ¥ 105 cells were seeded overnight in 35 mm dish, and then transiently transfected with the indicated plasmids together with pRL-TK (Promega) to measure the transfection efficiency. Expression plasmids were transfected in the following amounts: 0.1 mg pFA2-cJun (Stratagene); 0.2 mg pFR-Luc (Stratagene); 0.2 mg pNF-kB-Luc (Stratagene); 0.2 mg pRL-TK. Luciferase assays were performed using the Dual-Luciferase Reporter System (Promega), in which relative firefly luciferase activity was calculated by normalizing the transfection efficiency according to the activity of renilla luciferase. Relative firefly luciferase activity detected in the cell lysates is presented. The data shown indicate the mean SD (n = 3–4).
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Acknowledgements |
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Footnotes |
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Present address: Department of Physiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan. 
* Correspondence: E-mail: m.hagiwara.end{at}mri.tmd.ac.jp |
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Received: 12 September 2003
Accepted: 29 October 2003
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