Departments of 1 Internal Medicine and 2 Physiology, University of Michigan, Ann Arbor, Michigan 48104; and 3 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892
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ABSTRACT |
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Induction of the inducible cyclooxygenase isoform COX-2 is likely to be an important mechanism for increased prostaglandin production in renal inflammation. We examined the effect of lipopolysaccharide (LPS) on regional renal COX-2 expression in the rat. In the inner medulla, LPS injection (4 mg/kg ip) induced a twofold and 2.5-fold increase in the levels of COX-2 mRNA and COX-2 protein, respectively. In contrast, COX-2 expression in the renal cortex was not significantly altered. COX-2 promoter transgenic mice were created using the 2.7-kb flanking region of the rat COX-2 gene. In these animals, LPS injection induced reporter gene expression predominately in the inner medulla. The LPS receptor CD14, usually regarded as a monocyte/macrophage-specific marker, was found to be abundantly expressed in the inner medulla and in dissected inner medullary collecting duct (IMCD) cells, suggesting that it may mediate medullary COX-2 induction. CD14 was present only at low levels in cortex and cortical segments, including glomeruli. In cultured cells, it was abundant in mouse IMCD (mIMCD-K2) cells and renal medullary interstitial cells, but largely undetectable in mesangial cells and M1 cells, a cell line derived from mouse cortical collecting ducts. In the mIMCD-K2 cell line, LPS significantly induced COX-2 mRNA expression, with concomitant induction of CD14. LPS-stimulated COX-2 expression was reduced by the addition of an anti-CD14 monoclonal antibody to the culture medium. These results demonstrate that LPS selectively stimulates COX-2 expression in the renal inner medulla through a CD14-dependent mechanism.
cyclooxygenase-2; renal inner medulla; transgenic mice
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INTRODUCTION |
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CYCLOOXYGENASE (COX; prostaglandin-endoperoxide synthase EC 1.14.99.1) catalyzes the oxygenation and peroxidation of arachidonic acid to generate prostaglandin endoperoxides, the immediate precursors of a series of bioactive prostaglandins. Two distinct isozymes of COX have been identified, COX-1 and COX-2 (7, 9, 25, 27). COX-1 is constitutively expressed in a wide variety of tissues and organs, and is generally believed to have "housekeeping functions," especially in stomach, spleen, and kidney. Expression of COX-2, in contrast, can be rapidly induced, most dramatically in inflammatory cells, by proinflammatory stimuli such as cytokines, mitogens, and lipopolysaccharide (LPS). Selective inhibition of COX-2 has been shown to reverse inflammation in various tissues (1). Recently, large-scale clinical trials have demonstrated that COX-2 inhibitors are as potent as nonselective COX inhibitors, such as indomethacin and ibuprofen, in the treatment of various inflammatory diseases, but that they have fewer side effects in stomach and platelets (11, 23, 26). These observations are consistent with the initial speculation that COX-2 is the cytokine-inducible cyclooxygenase, critically involved in inflammatory responses (7, 16).
There is substantial evidence to demonstrate that LPS induces unique inflammatory responses in the kidney. Systemic infusion of LPS causes marked renal vasoconstriction, leading to a marked reduction of renal blood flow, despite a normal or increased cardiac output (2, 18). LPS also suppresses renin release (4, 28) and is associated with an immediate reduction of Na+ and K+ excretion followed by the development of profound natriuresis (19). It appears that local mechanisms underlie LPS-induced alterations in renal function. Prostaglandins are produced abundantly in the kidney, particularly in the inner medulla, and are capable of modulating multiple renal functions, such as renal blood flow (5, 34), renin release (33), and urinary Na+ excretion (3). LPS, infused systemically or administered intrarenally via the renal artery, has been shown to stimulate prostaglandin release from the kidney (29). These observations are consistent with the hypothesis that prostaglandins may be involved in the LPS-induced renal pathophysiology.
The mechanism of action of LPS has been extensively studied. LPS first induces hepatic LPS binding protein (LBP), which functions as a carrier protein in the circulation. The complex of LPS and LBP then recognizes and acts on CD14, which is located on the surface of macrophages (31). CD14 is a 5300-5500 mol wt glycosyl-phosphatidylinositol-anchored membrane protein that is found almost exclusively in monocytes and macrophages and that is often used as a marker of monocyte lineage. Large numbers of studies demonstrate that CD14 binds to LPS and LBP, and mediates LPS-induced cytokine production (6, 37). CD14, therefore, functions as the receptor for the LPS/LBP complex. In support of this notion, transgenic mice expressing human CD14 are hypersensitive to LPS (10).
The current experiments were performed to determine 1) whether treatment with LPS affects COX-2 expression in the kidney and whether the induction of COX-2 by LPS differs between different regions of the kidney, 2) whether LPS affects COX-2 promoter activity in transgenic mice in vivo, 3) whether renal epithelial cells express CD14, and 4) whether CD14 plays a role in LPS-regulated COX-2 expression in renal cells.
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METHODS |
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Animals. We performed experiments in male Sprague-Dawley rats (175-200 g). Rats in the experimental group (n = 16) received an intraperitoneal injection of 4 mg/kg Escherichia coli LPS (Sigma Chemical, St. Louis, MO). Rats in the control group (n = 16) received an intraperitoneal injection of the same volume of PBS. The animals were killed 2, 4, 6, and 8 h after LPS injection and tissue samples from renal cortex and inner medulla were harvested for the determination of COX-2 mRNA and protein. Animals were killed and tissue samples from renal cortex and inner medulla were harvested for the determination of COX-2 mRNA and protein. For RNA extraction, tissue samples were transferred immediately into microcentrifuge tubes containing 300 µl of TRI Reagent (Molecular Research Center, Cincinnati, OH) and snap frozen in liquid nitrogen. Samples from the other kidney were collected for protein analysis.
Cell culture experiments. The source of cultured cells, including mouse inner medullary collecting duct cells (mIMCD-K2), mouse cortical collecting duct cells (M1 cells), mesangial cells, and renal medullary interstitial cells (RMIC), has been described previously (39). To study the effect of LPS on COX-2 expression, we serum deprived confluent mIMCD-K2 cells for 12 h and then treated them with LPS (100 ng/ml) for various periods of time. To study the effect of CD14 receptor blockade on LPS-induced COX-2 expression, we serum deprived confluent mIMCD-K2 cells for 12 h and treated them with rmC5-3 (0.05 mg/ml; PharMingen, San Diego, CA), an antibody against recombinant mouse CD14, before stimulation with LPS.
cDNA synthesis and PCR.
Details of the methods used have been published previously (39). The
sequences of the oligonucleotide primers and their location in the
published cDNA sequences were as follows:
1) COX-2: sense 5'-ACA CTC TAT
CAC TGG CAT CC-3' (bp 1229-1248) and antisense 5'-GAA
GGG ACA CCC TTT CAC AT-3' (bp 1794-1813) were predicted to
amplify a product of 584 bp (9); 2)
CD14: sense 5'-GCA GCA GTG GCT AAA GCC TG-3' (bp
882-901) and antisense 5'-ATC GCC TCT TTG TTT AAG GAA
CAC-3' (bp 1185-1208) were predicted to amplify a product of
627 bp (12). We performed 30 PCR cycles with an annealing temperature
of 59°C for both COX-2 and -actin PCR and 60°C for CD14 PCR.
The quantitative assays used 10-fold serial dilutions of cDNA of each
experimental sample to ensure that all PCR determinations fell within
the linear amplification range. RNA samples subjected to the PCR
procedure without prior reverse transcription served as "reverse
transcriptase-minus" controls. Water and dissection medium blanks
were run to serve as a control for cDNA contamination. We checked
genomic DNA contamination by carrying samples through RNA isolation and
cDNA synthesis without the addition of reverse transcriptase.
Dissection medium and reverse transcriptase-negative samples
consistently yielded no product.
Western blotting analysis. Immunoblotting was performed as previously described (35). Briefly, kidneys were removed and tissue samples from cortex (200 µg) and inner medulla (100 µg) were dissected and homogenized. Tissue homogenates were suspended in loading buffer and subjected to electrophoresis on 10% SDS-PAGE. We transferred the contents of the gels electrophoretically to nitrocellulose membranes and stained them briefly with Ponceau S to determine uniformity of electrophoretic transfer. The membranes were then washed in TBS (20 mmol/l Tris · HCl, pH 7.5; 150 mmol/l NaCl; and 1% Nonidet P-40), blocked with 5% dry milk in TBS, and incubated with a 1:500 dilution of a COX-2 polyclonal antiserum (Cayman). The membranes were washed three times in TBS, blocked again, and incubated with 125I goat anti-rabbit IgG (ICN Biomedicals, Irvine, CA). Finally, we washed the filters three times in TBS, dried them, and quantitated them by phosphorimage analysis using a GS-250 Molecular Imager System and Phosphor Analyst software (Bio-Rad, Hercules, CA).
Experiments in transgenic mice. We amplified 2.7 kb of previously characterized rat COX-2 promoter sequence from genomic DNA isolated from liver of Wistar-Kyoto rats using a high-fidelity amplification kit (Boehringer Mannheim). The fragment was subsequently subcloned into pnlacf vector upstream of the nuclear localization signal and lacZ gene. The recovery of fertilized eggs, injection, and reimplantation into the oviducts of pseudopregnant female mice were performed with assistance from the Transgenic Core Facility at the University of Michigan (20). We performed genotyping by PCR using the chimeric, construct-specific primers. We obtained F1 mice by breeding the founder mice with CD-1 mice. After two intraperitoneally injected doses of LPS (1 mg/kg each), at 12 and 2 h before death, animals were anesthetized and perfused through the heart with 4% paraformaldehyde. Kidney was removed and cut into pieces. X-gal staining was performed at 30°C for 20 min, with the solution containing 0.2% X-gal, 10 mM sodium phosphate buffer (pH 7.0), 150 mM NaCl, 1 mM MgCl2, 3.3 mM K4Fe(CN)63H2O, and 3.3 mM K3Fe(CN)6.
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RESULTS |
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Effect of LPS on renal COX-2 mRNA and protein
expression in vivo.
The effect of a single injection of LPS on the renal expression of
COX-2 was determined in tissue samples from inner medulla and cortex.
We determined COX-2 mRNA and protein 2, 4, 6, and 8 h after LPS
injection by RT-PCR and Western blotting analysis, respectively. Under
basal conditions, COX-2 expression was more abundant in inner medulla
than in cortex, consistent with previous observations (13, 39). LPS
significantly enhanced COX-2 expression at both mRNA and protein levels
in the inner medulla, a change that was detectable 2 h after the
treatment and lasted over the next three time points. Because the
values derived from densitometric analysis of the four time points were
not significantly different, the data were pooled. The average increase
in COX-2 mRNA and protein in inner medulla after LPS treatment was
twofold and 2.5-fold, respectively. In contrast, COX-2 expression in
the cortex at either mRNA or protein levels was not significantly
altered by LPS. Figure 1 and Fig.
2 show representative gels of the effect of
LPS on COX-2 mRNA expression in inner medulla and COX-2 protein
expression in both cortex and inner medulla, respectively.
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Effect of LPS on COX-2 promoter activity in
vivo.
COX-2 promoter transgenic mice were created using a 2.7-kb rat COX-2
flanking sequence fused upstream of a nuclear localization signal and
lacZ. Genotyping was performed by PCR. Primers were selected
to span the junction region between promoter sequence and
lacZ gene, thus amplifying a product specific to the
chimeric construct (Fig.
3A).
The predicted 450-bp products were detected in tail DNA from the
transgenic mice, but not in that of CD-1 mice (Fig.
3B). Under basal conditions,
-galactosidase activity of both COX-2 transgenic and wild-type mice,
as well as of CD-1 mice, was detectable at low levels in cortex and
outer medulla, but not in inner medulla, despite a 12-h incubation. In
contrast, LPS treatment induced a marked increase in the
-galactosidase activity in the kidney, predominately in inner
medulla of a transgenic founder mouse (Fig.
4, A and
B). In the example shown in Fig. 4,
the intense staining was detected within 15 min after the incubation with X-gal. A similar pattern of staining was also observed in three
other LPS-treated F1 mice from a separate founder mouse (Fig.
4C), although intensity of staining
varied.
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Distribution of CD14 and LBP mRNAs in kidney
regions.
RT-PCR for CD14, LBP, and -actin was performed on 1 µg of total
RNA from cortex and inner medulla of adult Sprague-Dawley rats (Fig.
5). The identity of the products was
confirmed by restriction digest (data not shown). CD14 mRNA was
abundantly present in inner medulla, whereas the signal was barely
detectable in cortex. LBP mRNA was present in both regions, with a
modestly higher abundance in inner medulla than in cortex.
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Localization of CD14 in microdissected nephron
segments.
We determined CD14 mRNA expression in microdissected nephron segments
using RT-PCR. An abundant amount of CD14 mRNA was consistently detected
in inner medullary collecting ducts (IMCD; Fig.
6). Low levels of expression
were also regularly detected in glomerulus. Products were not
consistently observed in proximal convoluted tubule, cortical
collecting ducts, cortical thick ascending limb, or arcuate artery.
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mRNA expression in cultured cells of kidney
origin.
mRNA expression of CD14 was assayed in cultured cells of renal origin,
including two types of cortical cells (mesangial cells and M1 cells)
and two types of medullary cells (mIMCD-K2 and RMIC). Total RNA from
confluent cells was isolated and was subjected to RT-PCR. The CD14
signal (from undiluted cDNA) was abundantly present in mIMCD-K2 and
RMIC, the two medullary cells, but the signal was only detected at an
~100-fold lower abundance in mesangial and M1 cells, the two cortical
cell lines (Fig. 7), consistent with the
regional distribution pattern of CD14 shown in Fig. 5.
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Effect of LPS on COX-2 and CD14 mRNA expression in
cultured mIMCD-K2 cells.
Confluent mIMCD-K2 cells were serum deprived for 12 h and then treated
with LPS (100 ng/ml) for 4 and 16 h. PCR for CD14 and COX-2 was
performed on 1:10 and 1:100 diluted cDNA, ,and PCR for -actin was
performed on 1:100 and 1:1,000 diluted cDNA. Treatment of LPS (100 ng/ml) significantly stimulated both CD14 and COX-2 mRNA expression in
a time-dependent manner. Stimulation of CD14 peaked at 4 h and declined
at 16 h (Fig. 8), whereas stimulation of
COX-2 occurred at 4 h and peaked at 16 h after the treatment (Fig. 8).
To test the role of CD14 in mediation of LPS-stimulated COX-2
expression, we used CD14 antibody to neutralize CD14. As shown in Fig.
9, addition of the CD14 monoclonal antibody
significantly reduced LPS-stimulated COX-2 mRNA expression in cultured
mIMCD-K2 cells.
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DISCUSSION |
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In contrast to the constitutive presence of COX-1 in many organs and tissues, COX-2 is a cyclooxygenase isozyme that is characterized by absent or low expression under resting conditions and whose production is dependent on stimulation by cytokines, mitogens, and a variety of tissue-specific activators (7). However, COX-2 has been found in the kidney in the absence of specific interventions that typically stimulate its expression. The vast majority of renal constitutive COX-2 production in rats and humans is found in the medulla, both in RMIC and collecting duct cells (39). In addition, a highly localized expression of COX-2 in macula densa cells and/or surrounding thick ascending limb cells is also present in the renal cortex (39). Commensurate with the character of COX-2 as a highly inducible enzyme, renal expression of COX-2 mRNA, as well as COX-2 protein, was found to be regulated by a number of interventions, including changes in dietary salt intake and ureteral obstruction (30, 39). The current study was designed to determine the effects of in vivo and in vitro LPS treatment on renal COX-2 expression because LPS treatment has been shown to be a potent stimulator of de novo expression of COX-2 in cells that do not express it under resting conditions (17, 22).
Our data show that LPS caused a sustained upregulation of COX-2 mRNA and protein in the renal medulla, but not in the cortex. The inner medullary cells affected by LPS include IMCD cells, based on the present RT-PCR determinations in cultured mIMCD-K2 cells. The time course of LPS-stimulated COX-2 expression is similar to that reported earlier for induction of the enzyme by LPS in macrophages (38). Upregulation of COX-2 activity is consistent with several reports showing increased renal prostaglandin production after LPS treatment (19). In one previous study, LPS administered in a comparable dose to conscious rats did not affect the expression of COX-2 mRNA in kidney tissue (36). The present results would suggest that the stimulatory effect of LPS on medullary COX-2 may have been compensated by an opposite effect in the cortex, resulting in an absent net effect for the whole kidney.
The differential response is also seen in COX-2 promoter transgenic
mice. The transgenic mice were created using a 2.7-kb rat COX-2
flanking sequence fused upstream of nuclear localization signal and
lacZ. Under basal conditions, there was barely detectable -galactosidase activity in the kidney of the transgenic mice, not
consistent with the constitutive COX-2 expression in the kidney of
wild-type mice. It is possible that the regulatory elements responsible
for the constitutive expression of COX-2 in the kidney are located
outside the 2.7-kb flanking region of the COX-2 gene, that the
transgene is not integrated correctly into the chromosome, or that the
staining method is not sensitive enough to detect the low level of
constitutive reporter activity. We found that these animals exhibited
high responsiveness to LPS treatment by expressing the reporter gene
predominately in the renal medulla, consistent with the LPS-induced
COX-2 expression pattern in the kidney, suggesting that the 2.7-kb
flanking region contains LPS-responsive elements. We observed a certain
degree of variability in intensity of reporter activity between
different founder lines that may be due to differences in integration
sites in chromosomes.
The mechanisms responsible for the differential effect of LPS on COX-2 expression are unclear. However, expression of a number of genes, including COX-2 and bNOS, has been shown to be differentially regulated in the two regions; for example, salt restriction stimulates the expression of bNOS and COX-2 in the cortex, whereas salt loading stimulates their expression in renal medulla. Thus it is not unprecedented that cortical and medullary COX-2 are subject to differential regulation by LPS. However, the observation of renal expression of CD14 in the present study may provide a clue to understanding the mechanism for the differential regulation of renal COX-2 by LPS. CD14 is a glycosyl-phosphatidylinositol-anchored membrane protein that is regarded as a marker of monocyte/macrophage lineage. The expression of CD14 has been reported to be restricted to monocytes, neutrophils, and macrophages. Thus our finding of constitutive expression of CD14 in the kidney was unexpected. Consistent with predominant CD14 expression in the renal medulla, we found that CD14 expression was much more abundant in mIMCD-K2 cells and RMIC compared with cells derived from cortex, such as mesangial cells and M1 cells. These findings suggest that CD14-expressing medullary cells may behave like macrophages, being capable of responding to inflammatory stimuli with the induction of COX-2 and possibly of cytokines. In support of this idea, we demonstrated that, in the mIMCD-K2 cell line, LPS treatment significantly induced COX-2 mRNA expression with concomitant induction of CD14 expression. Furthermore, we significantly reduced the LPS-stimulated COX-2 expression by adding a CD14 monoclonal antibody to the culture medium. Taken together, this demonstrates the presence of both constitutive and inducible expression of CD14 in the renal medulla that is, at least in part, responsible for the site-specific induction of COX-2 in renal medulla by LPS.
Involvement of a medullary NO system may be another reason for the different response of COX-2 to LPS in cortex and medulla. The renal medulla is known to be a rich source of NO production (40), in agreement with the abundant expression of nitric oxide synthases (NOS), including the cytokine-stimulatable or inducible form of NOS, iNOS or NOS II (24). Stimulation of iNOS production by LPS may therefore be more pronounced in the medulla than in the cortex. Because NO has been shown, in a number of preparations, to stimulate COX activity (8, 32), it is conceivable that the medullary localization of COX-2 activation by LPS reflects the local interaction with inner medullary iNOS.
Mesangial cells are known to play a role in the pathogenesis of various
types of glomerular nephritis. In support of this notion, mesangial
cells in vitro are capable of responding to different inflammatory
interleukins by producing prostaglandins. Studies by Guan et al. (14,
15) have shown that interleukin-1 induces COX-2 expression in
cultured mesangial cells through a MAPK-mediated pathway. The low
expression of CD14 in mesangial cells shown in the present study
suggests that COX-2 stimulation during inflammation in these cells may
primarily reflect an indirect response to cytokines such as
interleukins rather than a direct response to LPS. It was an unexpected
finding, however, that LPS did not detectably increase mRNA and protein
levels of COX-2 in the renal cortex, suggesting a complex mechanism for
the in vivo regulation of COX-2. It is possible that COX-2 in mesangial
cells in vivo is stimulated by LPS through an indirect mechanism. The stimulation of COX-2 in mesangial cells may be compensated by inhibition of expression in tubular segments. In preliminary
observations, we found that COX-2 expression in thick ascending limb
was downregulated by LPS (data not shown). Future studies need to
examine the detailed mechanism for the differential response at the
cellular level.
The kidney is an organ that serves excretory and endocrine functions, but it has been recognized as an organ important in immune responsiveness as well. In certain aspects, differentiated kidney cells resemble immune cells with a potential to produce different cytokines in response to proinflammatory stimuli. For example, isolated renal interstitial cells in culture have been shown to produce cytokines, whereas skin fibroblast cells in the same condition did not (21). Clinical studies have shown that renal failure is frequently accompanied by severe infections that, in many instances, cannot be reversed by dialysis. Loss of renal immune function is likely to contribute to the infections seen in renal failure. On the other hand, disturbance of the renal immune system is known to be linked to various types of acute or chronic nephritis. Demonstration of CD14 in renal medulla and its role in LPS-stimulated medullary COX-2 expression is strong evidence in support of an important role of the kidney, particularly of the renal medulla, in immune response.
In summary, these studies report differential regulation of COX-2 expression in renal cortex and inner medulla by LPS. LPS stimulates COX-2 expression only in the renal inner medulla and not in the cortex. CD14, the LPS receptor, was found constitutively and selectively expressed in the inner medulla and in cultured cells derived from renal medulla. In the mIMCD-K2 cell line, LPS significantly induced COX-2 mRNA expression, with concomitant induction of CD14 and the LPS-stimulated COX-2 expression was reduced by the addition of CD14 monoclonal antibody to the culture medium. These results demonstrate that LPS selectively stimulates COX-2 expression in renal inner medulla through a CD14-dependent mechanism.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge Bruce Stanton for providing mIMCD-K2 cells and Richard Palmiter for providing pnlacf plasmid.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-37448, DK-39255, and DK-40042. Support was provided, in part, by the General Clinical Research Center (GCRC) at the University of Michigan, funded by a grant (M01RR00042) from the National Center for Research Resources, National Institutes of Health, US Public Health Service.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. Schnermann, NIDDK, NIH, Bldg. 10, Rm. 4DA51, 10 Center Dr., Bethesda, MD 20892-1370 (E-mail: jurgens{at}intra.niddk.nih.gov).
Received 27 August 1998; accepted in final form 3 March 1999.
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