Mol. Hum. Reprod. Advance Access originally published online on August 3, 2006
Molecular Human Reproduction 2006 12(10):619-624; doi:10.1093/molehr/gal067
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Interleukin-1-induced NF-
B recruitment to the oxytocin receptor gene inhibits RNA polymerase II–promoter interactions in cultured human myometrial cells
1Department of Obstetrics and Gynecology, 2Sealy Center for Molecular Science, 3Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA
4 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555-1062, USA. E-mail: msoloff{at}utmb.edu
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Abstract |
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The myometrial oxytocin receptor (OTR) is highly regulated during pregnancy, reaching maximal concentrations near term. These levels are then abruptly reduced in advanced labour and the post-partum period. Our goal was to examine the molecular basis for this reduction, using chromatin immunoprecipitation (ChIP). Interleukin-1
(IL1A) treatment of cultured human myometrial cells has previously been shown to reduce steady-state levels of OTR mRNA. We show further that IL1A reduced RNA polymerase II cross-linking to the otr promoter, as reflective of transcriptional inhibition. IL1A also increased the recruitment of nuclear factor 
B (NF-B) to a site 955 bp upstream from the transcriptional start site. Inhibition of NF-B activation negated the effects of IL1A on polymerase II dissociation, indicating a causal relationship, at least in part, between recruitment of NF-B and detachment of polymerase from the otherwise constitutively active otr promoter. IL1A treatment also resulted in increased histone H4 acetylation in the otr promoter region. Whereas NF-B recruitment and histone acetylation are generally associated with activation of gene expression, our findings show that both processes can be involved in dissociation of RNA polymerase II from an active promoter. The results of these studies suggest that the elevation of IL1 in the myometrium occurring at the end of pregnancy initiates the process of down-regulation of OTRs in advanced labour, resulting in the desensitization of the myometrium to elevated levels of OT in the blood during lactation.
Key words:
chromatin immunoprecipitation/interleukin-1/myometrial cell/NF-B/oxytocin receptor
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Introduction |
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Oxytocin (OT) is one of the most potent stimulators of uterine smooth muscle contractile activity and is thought to play an important role in labour. The sensitivity of the myometrium to OT is maximal at the end of gestation and generally corresponds with the concentration of OT receptors (OTRs) (Fuchs et al., 1983
), which are up-regulated during pregnancy and are maximal in the early stages of labour in virtually all species examined (Jeng et al., 2003). Following parturition, myometrial OTR levels fall sharply and the uterus becomes refractive to OT. In contrast, OTRs are up-regulated in the mammary myoepithelial cells during lactation to permit OT-stimulated milk ejection (Soloff et al., 1979). Thus, differential OTR regulation in the myometrium and mammary gland allows switching on or off of target cells at different stages of the reproductive cycle. Previous work from this laboratory using a cell line derived from human myoepithelial cells showed that constitutive expression of the human otr is regulated by the transcription factors GABP/ß and cFos/cJun, bound to cognate sites in the promoter region (–85 to –65 from the transcriptional start site) (Hoare et al., 1999). Similarly, OTRs are constitutively expressed in cultured human myometrial cells (Jeng et al., 2003). However, little is known of the in vivo molecular mechanisms that up-regulate OTR expression in the myometrium during pregnancy or that are involved in the down-regulation during late labour (Fuchs et al., 1982) and in the post-partum period. In the latter instance, homologous and heterologous OTR desensitization, possibly due to internalization, might be involved (Phaneuf et al., 2000). In addition, several laboratories have shown that treatment of cultured human myometrial cells with the proinflammatory cytokine interleukin-1 (IL1) caused a decrease in steady-state OTR mRNA levels (Rauk and Friebe-Hoffmann, 2000; Schmid et al., 2001; Helmer et al., 2002), but the mechanisms involved have not been examined in detail. IL1 levels in the rat and human myometrium are maximal in late pregnancy (Melendez et al., 2001; Winkler et al., 2001; Helmer et al., 2002) and the myometrium contains IL1 receptors (Hatthachote and Gillespie, 1999), and therefore, it is possible that IL1 plays a physiological role in helping down-regulate myometrial OTR concentrations in vivo after labour initiation. Expression of a human otr promoter-driven reporter plasmid transiently transfected into human epithelial carcinoma cells (HeLa) was inhibited by IL1 treatment (Schmid et al., 2001). As promoter activity is influenced by chromatin regulatory functions, transcriptional regulation of transiently transfected promoter sequences can differ from an integrated and/or endogenous promoter (Burkhart et al., 2005). The endogenous OTR gene is not transcriptionally active in HeLa cells, and so, the effects of IL1 treatment on the transfected OTR gene might not reflect regulation of the endogenous gene in human myometrial cells. Accordingly, we have utilized in situ chromatin immunoprecipitation (ChIP) analyses to examine the effects of IL1 signaling on the transcriptional machinery of the otr promoter in cultured human myometrial cells.
A major component of the IL1 signaling cascade in a variety of cell types, including myometrial cells (Belt et al., 1999), is the activation of the transcriptional regulatory nuclear factor B (NF-B) family (O’Neill, 1995). These transcription factors exist in most vertebrates cell types as homodimer and heterodimers of five structurally related proteins: NF-B1 (p50) and its precursor (p105), p52, RelA (p65), RelB and c-Rel (Baldwin, 1996; Ghosh et al., 1998). The most abundant activated forms are the RelA/p50 and RelA/p52 complexes. Other dimeric complexes, such as p50/p50, p52/p52, RelA/RelA homodimers and RelA/c-Rel heterodimers, have been detected in some cell types under certain culture conditions. However, the transactivational properties of these complexes have yet to be elucidated. In non-stimulated cells, NF-B is sequestered in the cytoplasm via interaction with IBs (Baeuerle and Baltimore, 1988). IL1 treatment stimulates the phosphorylation of IB, targeting it for ubiquitination and degradation through the 26S proteasome pathway (Liou and Baltimore, 1993). As IB masks the nuclear localization signal of NF-B in the cytosol, its degradation allows the translocation of NF-B to the nucleus where it interacts with binding sites (B elements) on target genes (Beg et al., 1992; Zabel et al., 1993).
The human otr contains a putative B element (Figure 1), about 955 bp upstream from the transcriptional initiation site (Inoue et al., 1994). The results of gross deletion analysis, using transient expression analysis in HeLa cells, suggest that this region could be involved in IL1-induced promoter inhibition (Schmid et al., 2001). However, there have been no studies to date demonstrating whether NF-B interacts with this site or whether NF-B binding is associated with the inhibitory actions of IL1 on the transcriptional properties of the OTR gene. Our data show that NF-B recruitment to the 955-bp upstream region is involved in the transcriptional repression of the otr promoter.
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Materials
Primer sets for the human genes U6 snRNA (–245/+85) and il8 (–121/+61 and –1042/–826) were reported previously (Nissen and Yamamoto, 2000
). Primer sets for the otr were 5'-GAGTGAGGCAGGGGTGTTT-3' and 5'-CAAGGGGTGGCAGGCAGTA-3' (–1113/–844), containing the putative NF-B site; 5'-GGAGAGAAAAGCCTGAAAA-3' and 5'-CTGCGAGAGGGAGGGAACT-3' (–218/–29); and 5'-ACCAAGAAAGGAAGAAACGGGCGGG-3' and 5'-CGAGGCCAGCCGCGCAGACC-3' (–81/+69) (Figure 1). The specificities of the PCR-amplified products were verified by cloning into pCRII (Invitrogen, Carlsbad, CA) and DNA sequencing. Rabbit polyclonal antibodies to p65 (sc-109), C/EBPß (sc-150) and polymerase II (sc-899) were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Polyclonal antibodies to residues 1–20 of histone H3 (06–599) containing acetylated lysines at positions 9 and 14 and residues 2–19 of histone H4 (06–598) containing acetylated lysines at positions 5, 8, 12 and 16 were obtained from Upstate (Waltham, MA). Antibodies to NF-B family members, in concentrated form for electrophoretic mobility shift assays (EMSA), were obtained from Santa Cruz Biotechnology. They included anti-p65 (sc-372X), -p50 (sc-1191X), -p52 (sc-298X), -cRel (sc-272X) and -RelB (sc-226X). Protein A/G PLUS-Agarose was also obtained from Santa Cruz Biotechnology. Recombinant human IL1A was purchased from R&D Systems (Minneapolis, MN). The proteasome inhibitor MG-132 was purchased from Biomol (Plymouth Meeting, PA).
Myometrial cell culture
The University of Texas Medical Branch Committee on Research Involving Human Subjects approved the use of human tissue. Myometrial samples were taken from women by Caesarean section near the end of gestation. Cells were prepared as described previously and maintained in minimum essential medium (MEM) containing 10% (v/v) fetal bovine serum (Atlanta Biological, Atlanta, GA), 1 mM sodium pyruvate, 2 mM L-glutamine, penicillin G (100 IU/ml), streptomycin sulphate (100 µg/ml) and amphotericin B (15 µg/ml) at 37°C (95% humidity) in the presence of 5% CO2 (Echetebu et al., 1999). The cells, which were used at confluency between passage 2 and 10, were serum-starved for 4 h before treatment. Cells were treated with IL1A (2 ng/ml) for 30 min. In separate studies, the cells were pre-incubated with either MG-132 (50 µM) or the dimethylsulphoxide vehicle for 1 h before addition of IL1A.
ChIP
ChIP analysis was carried out according to published procedures (Nissen and Yamamoto, 2000; Shang et al., 2000). Cells were fixed in 1% formaldehyde for 15 min, lysed in modified RIPA solution (10 mM Tris–HCl, pH 7.6, 0.5 mM EGTA, 1 mM EDTA, 140 mM NaCl, 0.025% NaN3, 1% Triton X-100, 0.1% sodium dodecyl sulphate (SDS), 1% deoxycholic acid, 1 mM phenylmethylsulphonyl fluoride, 1 µg/ml of leupeptin and 1 µg/ml of pepstatin A). The lysates were sonicated at 4°C under conditions determined empirically to yield DNA fragments of an average size of about 500 bp. The same lysate pool was used with each antibody examined. Lysate containing the same amount of DNA (5–10 µg) was mixed with the appropriate rabbit polyclonal IgG, 2 or 4 µg, overnight at 4°C. Protein A/G agarose beads (40 µl of a 50% slurry in lysis buffer containing sheared salmon DNA, 100 µg/ml) were then incubated with lysate for 2 h at 4°C. The beads were rinsed successively in lysis solution, Rinse 1 (10.0 mM Tris–HCl, pH 7.6, 500 mM NaCl, 0.025% NaN3, 1% Triton X-100, 0.1% SDS, 1% deoxycholic acid, containing salmon sperm DNA, 100 µg/ml), Rinse 2 (10.0 mM Tris–HCl, pH 8.0, 250 mM LiCl, 0.5% NP-40, 0.5% deoxycholic acid, 1 mM EDTA), Tris-buffered saline (TBS) and then eluted by incubating with 100 µl of 1% (w/v) of SDS in Tris–EDTA (10 mM/1 mM) for 10 min at 65°C. The eluate was deproteinized by incubating with 10 µg of proteinase K in an equal volume of Tris–EDTA for 1 h at 55°C. The cross-links were then reversed by further incubation at 65°C for 6 h. The DNA was purified by phenol/chloroform extraction and ethanol precipitation.
PCR was performed using doubling concentrations of DNA to ensure that amplification was linear, and amplicons were detected by ethidium bromide staining after agarose gel (2.0%) electrophoresis. Cells prepared from at least two patients were examined separately. The experiments were repeated with each antibody several times to ensure reproducibility, and the results depicted in the figures are representative of each analysis. The ChIP experiments were carried out in conjunction with previous work on cyclooxygenase-2 and IL8 gene analyses (Soloff et al., 2004).
EMSA
EMSA was carried out as described (Mifflin et al., 2002). The sense strand of the double-stranded oligonucleotide probe containing the putative NF-B-binding site in the OTR gene has the sequence 5'-AAGAGAAGGGGCTTGCCCAAGGTC-3'. Competition experiments contained a 200-fold molar excess of unlabelled otr oligonucleotide or an oligonucleotide containing the consensus NF-B element in the light-chain enhancer (5'-AGTTGAGGGGACTTTCCCAGGC-3'). The C/EBP-binding site of the cox2 promoter was used as a non-specific oligonucleotide control (Mifflin et al., 2002). For supershift analyses, antibodies (2.0 µg) were added after the initial incubation period, and reactions were incubated for an additional 45 min before electrophoresis.
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Results |
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Previous analyses of the effects of IL1 on OTR gene expression involved measurement of steady-state mRNA levels (Rauk and Friebe-Hoffmann, 2000
; Schmid et al., 2001; Helmer et al., 2002). To determine whether the effects of IL1 were on transcriptional activity of the otr promoter, we examined RNA polymerase II occupancy of the promoter by ChIP analysis.
Treatment of the cells with IL1A for 30 min resulted in a substantial reduction in polymerase II cross-linking to the promoter region of the OTR gene (Figure 2, probe –218/–29). In contrast, there was no polymerase cross-linked to a region about 1 kb upstream from the transcriptional start site (probe –1113/–844), the region of the putative NF-B-binding site. To show that RNA polymerase II binding was specific, we also examined its cross-linking to the IL8 gene promoter, which has been shown previously to bind polymerase II in response to IL-1 treatment, and the small nuclear RNA U6 promoter, which is transcribed by polymerase III (Nissen and Yamamoto, 2000; Soloff et al., 2004) and serves as a negative control. As expected, IL1A induced polymerase II cross-linking to the il8 promoter but not to the U6 snRNA promoter (Figure 2).
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We have shown previously by ChIP analysis that IL1A induction of prostaglandin (PG) endoperoxide synthase-2 (COX2) and IL8 expression in the same human myometrial cells used in the present study is mediated by the recruitment of NF-B to cognate-binding sites in the respective promoter regions (Soloff et al., 2004). Computer-assisted analysis of the 5'-flanking sequence of the OTR gene revealed the presence of a consensus NF-B-binding site 950–960 bp upstream from the transcriptional start site (Figure 1). We determined the authenticity of this site by EMSA, using an oligonucleotide containing the putative element and nuclear extracts from cultured human myometrial cells either before (–, Figure 3A) or 30 min after (+, Figure 3A) treatment with IL1A. Nuclear extracts derived from non-treated cells were essentially devoid of the ability to form nucleoprotein complexes, whereas substantial complex formation occurred after IL1A treatment. Similar results were obtained using an end-labelled NF-B consensus oligonucleotide from the IgG light-chain enhancer (data not shown). The nucleoprotein complex formed with the otr probe was completely eliminated by addition of a 200-fold molar excess of either Ig (Figure 3A, oligo 1) or otr (Figure 3A, oligo 2) oligonucleotides. There was no competition using an oligonucleotide containing a C/EBPß-binding site from the COX2 gene promoter (Figure 3A, oligo 3). We next established the identities of NF-B family members interacting with the otr-binding site using antibody super shift analyses (Figure 3B). Incubation of nuclear extracts from IL1A-treated myometrial cells and labelled probe with antibody to either p50 or p65 (RelA) reduced the amount of nucleoprotein complex, and the p65 antibody resulted in a supershifted complex. In contrast, antibodies to other NF-B family members (RelB, cRel and p52) had no effect on the nucleoprotein complex. These findings suggest that the predominant activated NF-B family member in myometrial cells is the p65/p50 heterodimer and show that antibody to p65 can be used for ChIP analysis
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In agreement with the EMSA results, IL1A treatment of myometrial cells resulted in the in situ cross-linking of p65 to the –955 region of the OTR gene, as shown by ChIP analysis (Figure 4A, probe –1113/–844). IL1A also induced RelA cross-linking to its cognate site on the IL8 gene (positive control), whereas there was no detectable binding of p65 to the U6 snRNA gene (negative control) (Figure 4A). Surprisingly, p65 was also cross-linked to the otr promoter region (Figure 4A, probe –218/–29). In contrast, there was no p65 binding to a region further downstream (–81/+69) (Figure 4A). An examination of the sequence not overlapped by the two probes (–218/–81) contains a putative C/EBPß (also known as NF-IL6)-binding site at –181 (Figure 1). In several instances, the binding of NF-B to cognate sites on DNA involves interactions with C/EBPß to form ternary complexes between the two transcription factors and DNA-binding sites (Stein and Baldwin, 1993; Dunn et al., 1994; Kunsch et al., 1994; Mondal et al., 1994; Xia et al., 1997). Treatment of human myometrial cells with IL1A also causes an increase in the nuclear content of C/EBPß (Schmid et al., 2001). However, using ChIP analysis and PCR primers bracketing the C/EBPß-binding site, we were unable to detect any cross-linking of C/EBPß (Figure 4B, probe –218/–29). In contrast, IL1A stimulated an increase in C/EBPß binding to the il8 promoter (Figure 4B), as we have noted previously (Soloff et al., 2004).
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Chromatin modification can modify transcription. In general, histone acetylation accompanies activation, while deacetylation is associated with repression. Surprisingly, IL1A inhibition of OTR expression was accompanied by an increase in histone H4 acetylation in the otr promoter region but not in the region containing the NF-B element (Figure 4C). Histone H4 acetylation in the il8 promoter region was also induced by IL1A treatment (Figure 4C), as we have reported previously (Soloff et al., 2004). Histone H3 acetylation was minimal in all regions and was not increased by IL1A treatment (data not shown).
To reveal whether IL1A inhibition of polymerase cross-linking was mediated by NF-B, we treated myometrial cells with an inhibitor of NF-B activation. Pretreatment of cells with MG-132 (50 µM), a cell permeable and selective 26S proteasome inhibitor that interferes with NF-B dissociation from the inhibitory IB complex (Bush et al., 1997), maintained the constitutive association of RNA polymerase II with the otr promoter after IL1A treatment (Figure 5). As a positive control, MG-132 blocked IL1A-induced cross-linking of polymerase II to the cox2 promoter (Figure 5), confirming that NF-B plays a role in recruiting polymerase to the cox2 pre-initiation complex (Soloff et al., 2004).
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Discussion |
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Our findings support the observation that IL1 induces down-regulation of OTR expression in myometrial cells (Rauk and Friebe-Hoffmann 2000
, Schmid et al., 2001; Helmer et al., 2002) and further indicate that the down-regulation occurs at the transcriptional level. Thus, treatment of the cells with IL1A reduced the amount of polymerase II cross-linked to the promoter region. To elucidate the mechanisms involved, we examined the involvement of NF-B, a known mediator of IL1A action. IL1A treatment of human myometrial cells resulted in p65 interaction with a site around 955 bp upstream from the transcriptional start site of the OTR gene, as determined by both EMSA and ChIP analyses. RelA was also cross-linked to a region between –218 and –81, as deduced by differences in the results obtained using promoter probes to two regions (–218/–29 and –81/+69). The –218/–81 non-overlapping sequence that interacts with p65 does not contain an apparent B site but has a C/EBPß-binding site. Given that NF-B can interact with C/EBPß (see references in Results section), it is possible that this association accounts for the cross-linking of p65 to the –218/–81 region. However, we were unable to demonstrate occupancy of the C/EBPß-binding site, possibly because C/EBPß complexed to NF-B does not display the epitopic sites.
Proteasome inhibitors, such as MG-132, have been widely used to block NF-B activation. These agents inhibit both the degradation of IBs and the processing of the precursor (p105) of p50, a major NF-B component (Palombella et al., 1994; Hellerbrand et al., 1998). MG-132 inhibition of NF-B translocation to the nucleus negated the effects of IL1A on polymerase cross-linking to the otr promoter. These results indicate that diminution in expression of the OTR gene with IL1A treatment is mediated by NF-B activation, at least in part. The specific mechanisms of p65 interaction with the promoter can be considerably complex. Aside from synergistic interactions occurring between NF-B and C/EBPß (LeClair et al., 1992; Matsusaka et al., 1993; Stein et al., 1993), the Rel domain of p65 interacts with leucine zipper structures of c-Fos, c-Jun (Stein et al., 1993), probably ATF family members and CRE-BP1 (Kaszubska et al., 1993). The Rel domain can also interact with the zinc finger domain of Sp1 (Perkins et al., 1994) and the DNA-binding domain of the estrogen receptor (Stein and Yang, 1995). The RelA subunit of NF-B interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression (Ashburner et al., 2001). However, IL1A treatment resulted in an increase in histone H4 acetylation in the promoter region, suggesting that recruitment of histone deacetylating enzyme activity does not account for the repressive effects of IL1A. It is possible, however, that the interaction between histone acetyltransferases and p65 (Gerritsen et al., 1997; Perkins et al., 1997) allows subsequent H4 acetylation and modification of chromatin structure leading to dissociation of polymerase II from the otr promoter. Alternatively, changes in chromatin structure might account for the recruitment of repressors that interfere with the architecture of the basal transcriptional machinery.
Human parturition is associated with a significant increase in IL1B, IL6 and IL8 mRNA expression in the cervix and myometrium, likely due in part to the increased infiltration of neutrophils and macrophages (Winkler et al., 2000; Winkler et al., 2001; Osman et al., 2003). Subtraction hybridization and gene microarray analyses have revealed that the expression of additional inflammatory genes is elevated in the human myometrium during labour (Chan et al., 2002; Charpigny et al., 2003). Proinflammatory cytokines might contribute to the initiation of labour by stimulating the transcription of PG endoperoxide-2 (COX2), resulting in increased PGE2 and F2 synthesis by the decidua and fetal membranes (Romero et al., 1989; Mitchell et al., 1990; Lundin-Schiller and Mitchell, 1991). These PGs stimulate uterine contractions and are thought to participate in the induction of labour. There is also evidence of a role for NF-B in labour initiation (Lindstrom and Bennett, 2005; Mendelson and Condon, 2005). However, cytokines have also been shown to play a role in myometrial remodelling that begins around the time of labour and continues into the post-partum period. The production of the precursor of matrix metalloproteinase 9 (MMP-9), a major contributor to tissue remodelling in the human myometrium at parturition, is under the control of IL1 (Roh et al., 2000). Induction of MMP-9 gene expression involves multiple regulatory 5'-DNA elements, among which is a NF-B-binding site (Sato and Seiki, 1993; Gum et al., 1996). Thus, IL1 and the production of other cytokines by the myometrium around the time of labour may lead to the activation of NF-B, which alters transcriptional activity (either stimulatory or repressive) of a target-gene network involved in preparation of the myometrium for post-partum involution, including the down-regulation of OTRs. In support of this view, myometrial OTRs are down-regulated in vivo in advanced labour (Fuchs et al., 1982). Although we still do not understand the molecular basis of increased expression of OTRs in human myometrium during pregnancy, knowledge of factors that turn off transcriptional activity of the OTR gene allows the design of experiments to elucidate critical positive cis and trans regulatory factors in the context of chromatin structure.
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Acknowledgements |
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We thank Solweig Soloff for technical assistance. This work was supported by funds from Garland D. Anderson, Chairman, Department of Obstetrics and Gynecology.
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Submitted on May 25, 2006; resubmitted on June 23, 2006; accepted on June 29, 2006.
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