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-Chain Gene Expression Via an Intronic Element
* Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Sciences, Tokyo, Japan;
Allergy Research Center, Juntendo University School of Medicine, Tokyo, Japan;
Department of Pediatrics, Yamaguchi University School of Medicine, Yamaguchi, Japan; and
Taiho Pharmaceutical Co. Ltd., Saitama, Japan
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Abstract |
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RI, is a key regulatory molecule in the allergic reaction. By screening for cis-acting elements over the entire region of the human FcRI 
-chain gene, a sequence located in the fourth intron was revealed to serve as a repressor element. This element was recognized by a transcription factor, myeloid zinc finger protein 1 (MZF-1). Introduction of MZF-1 antisense inhibited the suppressive effect of the element on the -chain promoter and increased the mRNA for the -chain in KU812 cells, indicating that MZF-1 repressed human FcRI -chain gene expression via the element in the fourth intron. Furthermore, it was suggested that a cofactor binding with MZF-1, whose expression level was different among the cell types, was required for transcriptional repression by MZF-1. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI) plays a key role in the IgE-mediated allergic reaction. Cross-linking of FcRI with Ag-IgE complexes leads to release of a variety of potent mediators, such as histamine, leukotrienes, and PGs. FcRI is composed of three kinds of subunits, 
, , and 
, of which the -chain directly binds IgE, while the - and -chains are responsible for mediating intracellular signals. The -chain has been revealed to play an important role for amplifying the -chain-mediated intracellular signals (1, 2). Recently, it was also reported that the -chain enhanced maturation of the -chain and facilitated receptor transport to the cell surface by its association with the -chain (3). These findings indicate that repression of -chain gene expression is expected to be an effective strategy to suppress the allergic reaction both by reducing the intracellular signals and by decreasing the cell surface expression of FcRI.
FcRI is expressed on limited types of cells, such as mast cells, basophils, eosinophils (4), monocytes (5), Langerhans cells (6, 7), platelets (8, 9), and neutrophils (10). The - and -chain expression is specific for FcRI-expressing cells, while the -chain is also expressed in other kinds of cells to form functional receptors for IgG (FcRI, FcRIII) and IgA (FcR) (11, 12, 13, 14, 15). It is therefore predicted that the - and -chain gene expression is regulated in a cell type-specific manner, and this regulation is responsible for the cell type-specific expression of FcRI.
In addition, the -chain gene is mapped on chromosome 11q13, and this locus was shown to be related to atopic diseases (16). Studies by many groups have focused on the relationship between the nucleotide sequence variants of the -chain gene and atopic diseases, and several positive linkages were reported (17, 18, 19, 20), indicating that the nucleotide sequence polymorphisms may be related to the transcriptional regulatory activity.
Although the genomic structure of the human FcRI -chain gene was previously determined (21), the mechanisms that regulate the transcription of this gene are poorly understood. Recently, Akizawa et al. (22) analyzed the 5' noncoding region of the -chain gene and reported that two Oct-1 binding sites in the 5' untranslated region (UTR)2 were essential for activation of the promoter. Because enhancer or suppresser elements apart from a promoter existing in introns or 3' noncoding regions have often been reported to regulate the gene expression (23, 24, 25, 26), we screened for cis-acting elements over the entire region of the human -chain gene and analyzed transcriptional regulatory mechanisms through such elements.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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KU812 (human basophillic leukemia cell line) and Jurkat (human T cell line) cells were cultured in RPMI 1640 (Sigma-Aldrich, St. Louis, MO) containing 10% FBS (JRH Bioscience, Lenexa, KS), penicillin, and streptomycin at 37°C in a 5% CO2 incubator. HMC-1 (human mast cell line) was cultured in IMDM (Invitrogen, Groningen, The Netherlands) containing 10% FBS, penicillin, and streptomycin. HeLa (human epithelial cell line) cells were cultured in DMEM (Sigma-Aldrich) containing 10% FBS, penicillin, and streptomycin.
Plasmid construction
Human FcRI -chain genomic DNA fragments (f1–f6; see Fig. 1) were obtained from a human genomic library (Stratagene, La Jolla, CA). The fragments f1–f6 were inserted into pGL(-95/+102) (22), which had nt -95 to +102 of the human FcRI -chain gene, followed by a luciferase gene in pGL3-Basic (Promega, Madison, WI). The other plasmids in Fig. 1 were prepared using a Kilo-Deletion Kit (Takara, Kyoto, Japan). To insert nt 3810–4260 of the -chain gene at the downstream of the luciferase gene, this region was amplified by PCR using the synthetic oligonucleotides of 5'-gcggatccAGTAGAGACAGGGTTTCACCAT-3' and 5'-gcggatccGATGTGTTTCCCTTAAGACTCTT-3' (nucleotides represented by small letters were added to introduce BamHI sites (underlined)) as primers. After digestion with BamHI, the amplified product was inserted into pGL(-95/+102) at the BamHI site, and the sequence was verified. The regions nt 3810–4122 and nt 4180–4260 were respectively inserted into pGL(-95/+102) downstream of the luciferase gene at the SalI site using PCR, blunting, and restriction endonuclease digestion techniques. The latter resulting plasmid was named pGp-4180/4260. In addition, the region nt 4180–4260 was inserted into pGL(-95/+102) upstream of the promoter in the correct direction at SmaI/MluI site and in the reverse direction at the SmaI site. A series of mutant plasmids in Fig. 2B was constructed using the QuickChange Site-Directed Mutagenesis Kit (Stratagene).
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Luciferase assay
Cells were washed with medium including 20% FBS and then resuspended in the same medium at a concentration of 1 x 107 cells/500 µl. The cells were transfected with 5 µg of test construct by electroporation at 300 V and 950 µF using a Gene Pulser II (Bio-Rad, Hercules, CA). When MZF-1 sense or antisense was expressed, cells were cotransfected with 5 µg of reporter plasmid and 5–20 µg of pCR3.1-hMZF1sense or antisense. A plasmid pRL-CMV (Toyoink, Tokyo, Japan) carrying the Renilla luciferase gene under the control of the human CMV promoter was introduced to normalize transfection and cell lysis efficiency. After incubation for 24 h, cells were harvested and washed with PBS (pH7.4). Cell lysis and determination of the luciferase activity were conducted using a Dual-Luciferase Assay Kit according to the manufacturer’s instructions (Promega). Luminescence was measured with a Luminometer (Berthold, Postfach, Germany).
Nuclear extract preparation
KU812 cells were washed with ice-cold PBS and resuspended in ice-cold buffer A (10 mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM EDTA, 1 mM DTT, 1 mM PMSF, 1 µg/ml leupeptin, and 1 µg/ml aprotinin). The cells were incubated on ice for 10 min and for an additional 15 min with 0.5% Nonidet P-40. After centrifuging at 6,000 x g for 1 min, the pellet was resuspended in extract buffer (20 mM HEPES (pH 7.9), 400 mM KCl, 4.5 mM MgCl2, 0.2 mM EDTA, 1 mM DTT, 1 mM PMSF, 1 µg/ml leupeptin, and 1 µg/ml aprotinin) and incubated on ice for 1 h. The lysate was centrifuged at 10,000 x g for 10 min. After the addition of 15% glycerol, the supernatant was stored at -80°C until use.
Preparation of Escherchia coli extract
E. coli BL21 (Stratagene) was transformed with pGEX-hMZF1 or pGEX-4T2. A 0.01 vol of overnight culture of the transformed cells was inoculated into Luria-Bertoni medium containing 50 µg/ml ampicillin and cultured at 30°C until the OD600 reached 0.4–0.6. After the addition of isopropyl -D(-)-thiogalactopyranoside (Invitrogen) at a concentration of 0.2 mM, the cells were cultured for an additional 4 h. The cells were collected and washed with cold PBS. After one freeze-thaw cycle, the cells were destroyed by sonication with a Bioruptor (COSMO BIO, Tokyo, Japan). Soluble fractions were obtained by centrifugation at 15,000 x g for 10 min.
EMSA
Double-stranded DNA was prepared for a probe by annealing FITC-labeled synthetic oligonucleotides 5'-GTGAGTTGCCCGCTTCTGTCTTTG-3' and 5'-CAAAGACAGAAGCGGGCAACTCAC-3' (Invitrogen). Three nonlabeled, double-stranded oligonucleotides were similarly prepared to use as competitors. Their nucleotide sequences were as follows: self competitor (carrying the same sequence as the probe), 5'-GTGAGTTGCCCGCTTCTGTCTTTG-3'; mutant competitor (with three nucleotide substitutions in self competitor (underlined)), 5'-GTGAGTTGCTCGGTTATGTCTTTG-3'; and nonspecific competitor (carrying unrelated sequence), 5'-CTGTCTTTGTCCATCCTTGAAAAG-3'.
Thirty micrograms of nuclear extract and 5 pmol of DNA probe were incubated at room temperature with 5–125 pmol of competitors in 10 mM HEPES buffer (pH 7.9) containing 400 ng of poly(dI-dC), 1 mM MgCl2, 30 mM KCl, 1 mM DTT, and 5% glycerol. Similarly, 10 µl of E. coli extract containing recombinant GST-MZF1 fusion protein or GST alone was incubated with 5 pmol of DNA probe. After 20 min of incubation, the mixtures were analyzed by electrophoresis with 4% polyacrylamide gel at 120 V for 2–3 h in 0.5xTBE buffer (45 mM Tris, 45 mM boric acid, and 1 mM EDTA). The fluorescence of FITC was detected using a Fluor Imager 595 (Amersham Pharmacia Biotech).
RT-PCR
For an MZF-1 antisense expression assay in KU812 cells, 20 µg of pCR3.1-hMZF1antisense was introduced into 1 x 107 cells by electroporation. The empty plasmid, pCR3.1-self, was used as a control. After 12 h, G418 was added at a concentration of 0.4 mg/ml, and the cells were cultured for additional 48 h. Total RNA was prepared from the cells with TRIzol (Invitrogen). The mRNA for FcRI -chain and -actin were quantitated by RT-PCR using 1 µg of the prepared RNA as a template. The synthetic oligonucleotides shown below were used for PCR primers: FcRI -chain, 5'-ATGGACACAGAAAGTAATAGGAGAG-3' and 5'-CTTATAAATCAATGGGAGGAGACATT-3'; and -actin (28), 5'-CATCGAGCACGGCATCGTCACCAAC-3' and 5'-GTGTTGGCGTACAGGTCTTTGCGGA-3'. A thermal cycle of 94°C for 30 s, 55°C for 30 s, and 72°C for 1 min was repeated 28–32 times for the -chain and 18–22 cycles for -actin.
To detect FcRI -chain and MZF-1 mRNA in various cell lines, total RNA was prepared from each cell line with TRIzol (Invitrogen). For FcRI -chain and -actin, an RT reaction was performed using an oligo(dT) adaptor primer, followed by PCR (34 cycles for the -chain, 24 cycles for -actin) with the primers mentioned above. Nested PCR was performed for the -chain using 1/5000 of the first PCR product as a template and synthetic oligonucleotides of 5'-CCTCATCCCCACCACTGCATACATG-3' and 5'-GGTGAGAAACAGCATCATCACTACA-3' as primers (25 cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 1 min). For MZF-1 and GAPDH, after RT reactions using random hexamer primers, PCR was performed with oligonucleotide primers whose sequences are as follows (27, 29): MZF-1, 5'-CTTCAGCCGCAGCTCGCACCTGCT-3' and 5'-CTACTCGGCGCTGTGGACGCGCTGGT-3'; and GAPDH, 5'-CCACCCATGGCAAATTCCATGGCA-3' and 5'-TCTAGACGGCAGGTCAGGTCCACC-3'. A thermal cycle of 94°C for 30 s, 65°C for 30 s, and 72°C for 2 min was repeated 26–30 times for MZF-1 and 20–24 times for GAPDH.
Northern blotting
KU812 cells were transfected with 10 µg of pCR3.1-hMZF1antisense or pCR3.1-self and cultured for 12 h. After the addition of G418, the cells were cultured for additional 48 h, and total RNA was prepared. Ten micrograms of total RNA was electrophoresed on a 1.5% agarose gel containing 2.2 M formaldehyde at 80 V to be transferred to a Hybond N+ nylon membrane (Amersham Pharmacia Biotech). After prehybridization in 5x SSC containing 50% formamide, 1% blocking reagent (Roche, Basel, Switzerland), 0.1% N-lauryl salcosine, and 0.02% SDS overnight, the membrane was hybridized in the same buffer with the probe for the -chain at 37°C, followed by rehybridization with the probe for -actin at 50°C. Dioxygenin-labeled PCR products of FcRI -chain and -actin were generated as probes. The hybridized probe was detected with alkaline phosphatase-labeled anti-dioxygenin Ab and CDP-Star substrate (Roche).
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Results |
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The human FcRI -chain gene consists of seven exons, as shown in Fig. 1. For the first step to screen for cis-acting elements, six genomic DNA fragments (f1–f6) extending over the region from nt 105 to 11,750 of the -chain gene and their deletion constructs were tested for their transcriptional regulatory activity. Each of the fragments was inserted upstream of the -chain gene promoter in pGL(-95/+102) (22), which had nt -95 to nt 102 of the -chain gene containing the promoter region, followed by a luciferase gene. A human basophilic leukemia cell line, KU812, known to express mast cell-specific molecules, was used for the transient transfection assay. The luciferase activities relative to that of pGL(-95/+102) are shown in Fig. 1. Three regions of nt 3,810–4,260, nt 5,055–6,349, and nt 9,301–9,642 increased -chain promoter activity >3-fold, while the region nt 7,919–8,174 decreased it by less than one-third. Similarly, when a human mast cell line, HMC-1, also expressing the -chain gene was used for the assay, almost the same pattern was obtained (data not shown). Among these four regions showing enhancing or suppressing effects, further analyses were performed on the fragment nt 3,810–4,260. Because the region nt 3,810–4,260 is located downstream of the promoter on the original -chain gene, we first investigated whether the fragment had a regulatory activity when located downstream of the promoter. Unexpectedly, the fragment nt 3,810–4,260 gave a suppressive effect rather than an enhancing one downstream of the promoter in both correct and opposite directions (Fig. 2A). To determine the region responsible for this activity, we next generated deletion constructs and analyzed their activities. A DNA fragment nt 4,180–4,260 containing a part of the fourth intron decreased the luciferase activity to about one-fourth independently of its orientation downstream of the promoter, while the fragment nt 3810–4122 including the third intron part gave neither enhancing nor suppressing activity (Fig. 2A). This suggested that the fragment nt 4180–4260 contained a repressor element. Interestingly, the region nt 4180–4260 showed enhancing effects when located upstream of the promoter independent of its orientation (Fig. 2A) as did nt 3810–4260 upstream of the promoter. Therefore, it was thought that this element functioned as both a repressor and an enhancer depending on the position relative to the promoter.
Mapping of the repressor element
For further mapping of the repressor element in the region nt 4180–4260, a series of mutant reporter plasmids was constructed by substituting a few nucleotides in this region downstream of the luciferase gene and was used for a transient transfection assay in KU812 cells (Fig. 2B). Because the luciferase activity increased when three nucleotides around nt 4190 were exchanged (discriminated by a black bar in Fig. 2B), the region around nt 4190 was suggested to serve as a repressor element. This region included a sequence similar to a binding motif of a transcription factor MZF-1 (5'-TGCCCGCT-3' was similar to the complement sequence of consensus MZF-1 binding motif 5'-NGNGGGGA-3'.). We next analyzed the factor binding to the region by EMSA. Addition of the nuclear extract prepared from KU812 cells to a dsDNA probe including this element caused the appearance of several shifted bands (lane 2 in Fig. 3A). The band indicated by a white arrow disappeared after the addition of a self-competitor in a dose-dependent manner (lanes 3–5), while it was not affected by the addition of a nonspecific competitor (lanes 6–8). This observation showed that the band shift reflected on the sequence specific binding between the probe DNA and the nuclear protein. Furthermore, the competitive effect was significantly reduced when a mutant-type competitor with substitutions of three bases in the MZF-1 binding motif-like sequence was used (lanes 9–11), indicating that the nuclear protein specifically recognized the MZF-1 binding motif-like element.
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We next examined whether the binding factor recognizing the element was MZF-1. Because no Ab against MZF-1 was commercially available, a fusion protein of GST and human MZF-1 was produced in E. coli, and the recombinant protein was used for EMSA (Fig. 3B). The fact that the GST-MZF1 fusion protein, not GST alone, caused the appearance of a shifted band indicated that MZF-1 recognized the nucleotide sequence of the determined element. Furthermore, a s oligonucleotide containing a typical consensus sequence of MZF-1 binding motif clearly inhibited the binding between the probe and the NF in EMSA (data not shown). These results indicated that the NF binding to the element in the fourth intron was MZF-1.
MZF-1 antisense increased FcRI -chain expression
Next, we investigated whether MZF-1 repressed the FcRI -chain gene expression. For this purpose, human MZF-1 antisense expression plasmid was constructed and introduced into KU812 cells with a reporter plasmid carrying the -chain promoter and a luciferase gene with or without nt 4180–4260 of the -chain gene. The MZF-1 antisense increased luciferase activity in a dose-dependent manner in the presence of nt 4180–4260 and had no effect on the luciferase activity in the absence of nt 4180–4260 (Fig. 4A). Furthermore, MZF-1 antisense was introduced into KU812 cells to quantitate the mRNA for the -chain by RT-PCR (Fig. 4B) and Northern blotting (Fig. 4C). The introduction of MZF-1 antisense increased the amount of -chain mRNA 
2.5-fold, while the transfection of a control plasmid, pCR3.1-self, had no effect on -chain gene expression.
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RI -chain gene expression via an element in the fourth intron in human mast cells. Possibility of the presence of a cofactor
MZF-1 sense or antisense DNA was introduced into various cell lines with the reporter plasmid pGp-4180/4260. As shown in Fig. 5A, introduction of MZF-1 expression plasmid had different effects on the -chain promoter depending on cell types. Unexpectedly, overexpression of MZF-1 in KU812 and HMC-1 cells, both of which expressed the FcRI -chain mRNA abundantly (Fig. 5B), showed no remarkable suppressive effects on -chain promoter activity. In contrast, MZF-1 overexpression repressed -chain promoter activity in a human T cell line, Jurkat, that expressed small amounts of -chain mRNA (Fig. 5, A and B). The -chain promoter was not activated regardless of MZF-1 expression in a human epithelial cell line, HeLa, whose mRNA for the -chain was undetectable (Fig. 5, A and B). Because one of the possibilities was that endogenous MZF-1 was more abundant in KU812 and HMC-1 than in Jurkat, the amount of MZF-1 mRNA was analyzed by RT-PCR. The endogenous expression level of MZF-1was almost equal among these cell lines (Fig. 5C). These results collectively suggested that the presence of a cofactor, which was more abundant in Jurkat cells than in KU812 and HMC-1 cells, was required for the suppressive activity of MZF-1.
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Discussion |
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-chain gene, the region nt -95 to +102 was revealed to be essential for the cell type-specific activation of the promoter (22). The region nt -95 to +102 produced the promoter activity in -chain-positive cell lines KU812, HMC-1, and Jurkat, while it had no activity in a -chain-negative cell line HeLa (Fig. 5A, the top bar in each graph). However, the promoter activity did not show significant differences among KU812, HMC-1, and Jurkat despite the marked abundance of the -chain mRNA in KU812 and HMC-1 compared with Jurkat cells (Fig. 5B). These results suggested that elements apart from the promoter region determined the cell type-specific expression level in -chain-positive cells. Here we screened for cis-acting elements over the entire region of the human FcRI -chain gene and revealed that MZF-1 repressed -chain expression via an element in the fourth intron. MZF-1 is abundantly expressed in myeloid cell lineages (27). MZF-1-mediated suppressive regulation is thought to be one of the factors determining the cell type-specific expression level of the -chain in -chain-positive cells by modifying the promoter activity. In addition, if a cofactor interacting with MZF-1 is present, as suggested in Fig. 5, the expression level of the cofactor will also modify the -chain expression level. It is speculated that abundant expression of both MZF-1 and the cofactor suppresses -chain gene expression in cells where the core promoter is potentially active but little -chain mRNA is expressed, as seen in Jurkat. This coincides with the fact that T cells are known not to express FcRI on their surface. In fact, in the presence of the MZF-1-binding element, luciferase activity from the -chain promoter was near the basal level in Jurkat cells, and it decreased to almost less than the basal level after overexpression of MZF-1 (Fig. 5A). However, we do not exclude the possibility that other elements play essential roles in determining the cell type-specific expression level by enhancing promoter activity or inhibiting MZF-1-mediated suppression, specifically in -chain-expressing cells. MZF-1 is a transcription factor with 13 zinc finger motifs. It binds DNA, including the G-rich core motif, to both positively and negatively regulate target gene expression and has been reported to play an important role in myeloid cell differentiation (30, 31, 32, 33). The fact that MZF-1 both enhanced and suppressed target gene expressions depending on the cell type suggested the presence of cell type-specific cofactors. A domain composed of four zinc fingers at the N-terminal region and a domain of nine zinc fingers at the C-terminal region are shown to recognize and bind the motif sequence independently (34). Thus, it might be possible that one of the two DNA binding domains actually interacts with DNA depending on the binding of a specific cofactor, resulting in a specific interaction of MZF-1/cofactor complex with target DNA. It will be interesting to investigate the regulatory mechanism of the transcriptional suppression by MZF-1 in our case through analyses of their manner of interaction.
MZF-1 was up-regulated by GM-CSF (35), and the cell surface expression of FcRI was reported to be repressed by the addition of GM-CSF in HMC-1 cells, although -chain expression was not examined (36, 37). The overexpression of MZF-1 alone did not decrease -chain gene expression in HMC-1 cells, but it is possible that the up-regulated MZF-1 causes repression of -chain expression, cooperating with other factors induced by GM-CSF.
Some genomic DNA fragments, except nt 3810–4260, also increased or decreased luciferase activity, as shown in Fig. 1. We are currently analyzing the enhancing and suppressive activities of such regions. Two regions existing in 3'UTR significantly suppressed and increased luciferase activity, respectively. Because elements at the 3'UTR often contribute to translational, but not transcriptional, regulation through mechanisms such as mRNA stabilization or destabilization (38, 39, 40, 41, 42), the suppressive and enhancing activities of these regions at the 3'UTR will have to be analyzed for both transcriptional and post-transcriptional aspects.
The analyses of the transcriptional regulation of the FcRI -chain gene may provide a new target of therapeutic or preventive agents against allergy. For example, suppression of -chain gene expression by inhibiting or activating cell type-specific and/or situation-specific interaction between cis-elements and binding factors (and cofactors) is thought to be an efficient method to prevent allergic reaction by decreasing both the intracellular signaling and the cell surface expression of the receptor. More detailed studies will gradually reveal the entire mechanism of FcRI -chain expression.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: UTR, untranslated region; MZF-1, myeloid zinc finger protein 1.
Received for publication March 3, 2003. Accepted for publication June 27, 2003.
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B and activating transcription factor 2/Jun and translational regulation through the au-rich region of the 3' untranslated region. J. Immunol. 167:2202.-F1-ATPase mRNA depends on the regulation of a protein that binds the 3' untranslated region of the mRNA. Mol. Cell. Biol. 17:5255.[Abstract]This article has been cited by other articles:
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  K. Takahashi, N. Hayashi, T. Shimokawa, N. Umehara, S. Kaminogawa, and C. Ra Cooperative Regulation of Fc Receptor {gamma}-Chain Gene Expression by Multiple Transcription Factors, Including Sp1, GABP, and Elf-1 J. Biol. Chem., May 30, 2008; 283(22): 15134 - 15141. [Abstract] [Full Text] [PDF]
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 K. Takahashi, N. Hayashi, S. Kaminogawa, and C. Ra Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor beta-Chain Gene Induced by GM-CSF J. Immunol., October 1, 2006; 177(7): 4605 - 4611. [Abstract] [Full Text] [PDF]
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C. Nishiyama, Y. Akizawa, M. Nishiyama, T. Tokura, H. Kawada, K. Mitsuishi, M. Hasegawa, T. Ito, N. Nakano, A. Okamoto, et al. Polymorphisms in the Fc{epsilon}RI{beta} Promoter Region Affecting Transcription Activity: A Possible Promoter-Dependent Mechanism for Association between Fc{epsilon}RI{beta} and Atopy J. Immunol., November 15, 2004; 173(10): 6458 - 6464. [Abstract] [Full Text] [PDF]
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