Departments of 1 Nutritional Science and Dietetics and 2 Biochemistry, University of Nebraska at Lincoln, Lincoln, Nebraska 68583
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ABSTRACT |
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Biotin has been credited with having
beneficial effects on immune function despite observations that biotin
supplementation causes decreased secretion of interleukin-2. Here this
paradox was addressed by determining whether receptor-dependent
internalization of interleukin-2 by immune cells depends on biotin.
Theoretically, this would be consistent with both decreased net
secretion of interleukin-2 by biotin-supplemented cells (causing
increased endocytosis) and beneficial effects of biotin on immune
function (causing increased receptor signaling). Jurkat cells were
cultured in biotin-defined media (25, 250, or 10,000 pM). Secretion of interleukin-2 correlated negatively with biotin supply, but
transcriptional activity of the interleukin-2 gene correlated
positively with biotin supply, suggesting that decreased secretion of
interleukin-2 by biotin-supplemented cells was not caused by decreased
gene expression. Expression of the interleukin-2 receptor- gene was greater at 10,000 pM than 25 pM biotin, mediating increased endocytosis of interleukin-2 in biotin-supplemented medium. Inhibition of endocytosis by genistein and overexpression of interleukin-2
receptor-
abolished the effect of biotin. These findings suggest
that endocytosis of interleukin-2 depends on biotin.
cytokines; gene expression; propionyl-CoA carboxylase
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INTRODUCTION |
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TH1
lymphocytes respond to stimulation by antigens with transcription
of the gene encoding interleukin (IL)-2 (17). After secretion into the extracellular space, IL-2 binds to IL-2 receptors (IL-2R) located on the surface of T and B cells, natural killer cells,
and some myeloid cells (17). Three distinct IL-2 receptors have been identified in human cells: IL-2R, IL-2R
, and IL-2R
(17, 37). IL-2R
and IL-2R
are expressed
constitutively; in contrast, IL-2R
is expressed only in response to
stimulation of immune cells (39). IL-2R may associate on
the cell surface to form the following heteromers: 1)
high-affinity receptor: one molecule each of IL-2R
, IL-2R
, and
IL-2R
(Kd for IL-2 = 0.01 nM);
2) intermediate-affinity receptor: IL-2R
and IL-2R
(Kd = 1 nM); and 3) low-affinity
receptor: IL-2R
(Kd = 10 nM) (37, 39).
Binding of IL-2 to IL-2R triggers intracellular signaling cascades,
which involve phosphorylations of tyrosine kinases such as Jak3 and
signal transducers such as Stat5 (17, 37). These cascades
lead to growth and differentiation of immune cells (17, 31,
37). Signal transduction depends on IL-2R, suggesting a
pivotal role of IL-2R
in the human immune response (37,
39).
Ultimately, IL-2-IL-2R complexes are endocytosed and degraded
(14, 15, 25, 36, 38, 41, 42) to avoid excessive stimulation of the immune system by IL-2. IL-2R is endocytosed less
extensively than IL-2R
and IL-2R
, and the majority of endocytosed IL-2R
is recycled to the cell surface (15, 25, 36, 41, 42).
Numerous studies have provided evidence for an essential role of the
vitamin biotin in immune function (3, 7, 18, 28-30).
In previous investigations we determined whether beneficial effects of
biotin supplementation on immune function are mediated by increased
secretion of IL-2. Surprisingly, we observed (21, 43) that
secretion of IL-2 was negatively correlated with cellular biotin supply
in freshly isolated human lymphocytes and in Jurkat cells. In the
present study we hypothesized that expression of IL-2R (and thus
endocytosis of IL-2) is dependent on biotin concentrations in immune
cells. This hypothesis is consistent with decreased (apparent)
secretion of IL-2 by biotin-supplemented cells (because of increased
endocytosis) despite the beneficial effects of biotin supplementation
on immune function (because of increased IL-2 signaling activity). A
human lymphoid cell line (Jurkat cells) that expresses IL-2R and
IL-2R
(12, 14) was used to test this hypothesis.
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MATERIALS AND METHODS |
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Cells and culture conditions. Jurkat cells (clone E6-1) were purchased from American Type Culture Collection (Manassas, VA). Cells were cultured (5% CO2 at 37°C in humidified atmosphere) in the following biotin-defined media for at least 5 wk before sample collection: 25 pM biotin (denoted "deficient"), 250 pM biotin ("physiological"), or 10,000 pM biotin ("pharmacological"); culture medium was replaced with fresh medium every 48 h. Media were prepared as described previously (21); biotin concentrations in media were confirmed by an avidin-binding assay (22) with modifications (21).
Biotin concentrations in media were chosen on the basis of the following lines of reasoning. Two hundred fifty picomolar biotin equals the physiological concentration of biotin in plasma from healthy adults (23). Twenty-five picomolar biotin is more than two standard deviations below the mean physiological concentration in normal plasma (23) and thus equals a deficient concentration of biotin. Ingestion of a typical biotin supplement providing 25 times the adequate intake of biotin for adults (26) is associated with plasma concentrations of ~10,000 pM biotin in healthy adults (43); thus this concentration represents a pharmacological concentration of biotin in plasma. Cell viability was monitored at timed intervals by using Trypan blue as previously described (44); viability of cells was 98-100%. Consistent with this finding, previous studies showed that activities of the enzyme caspase-3 (marker for apoptosis) are below the limit of detection when Jurkat cells are incubated in media containing 25-10,000 pM biotin (21).Propionyl-CoA carboxylase activity. Biotin serves as a coenzyme for propionyl-CoA carboxylase (PCC). Activities of PCC were quantified in cell extracts to confirm that intracellular biotin concentrations correlated with the biotin concentrations in media. The carboxylase assay quantifies the binding of radioactive bicarbonate to propionyl-CoA, catalyzed by PCC in samples of lysed cells. The assay was conducted as described previously (46) with modifications (21).
Secretion of IL-2. Secretion of IL-2 was induced by incubating 106 Jurkat cells with 50 µg/l of phorbol 12-myristate 13-acetate (PMA) and 2 mg/l of phytohemagglutinin (PHA) in a final volume of 260 µl as described previously (21). Times of stimulation varied among experiments and are specified in RESULTS. Cell-free medium supernatant was collected by centrifugation and analyzed for IL-2 with a commercial ELISA (hIL-2 EAISA; Biosource, Camarillo, CA) as described previously (21).
In the present study we hypothesized that the increased (apparent) secretion of IL-2 by biotin-deficient cells (21, 43) is caused by decreased endocytosis of IL-2 by these cells. Thus inhibitors of endocytosis should theoretically abolish effects of biotin on net secretion of IL-2. To test this hypothesis, cells were stimulated with PMA and PHA for 6 h as described above in the presence of 250 µM genistein. Inhibition of tyrosine kinases by genistein is known to inhibit endocytosis of IL-2 (42). Cell-free supernatants were collected and assayed for IL-2 as described above.Reverse transcriptase polymerase chain reaction.
mRNA encoding IL-2, IL-2R, IL-2R
, and glyceraldehyde-3-phosphate
dehydrogenase (G3PDH; control) were quantified by reverse transcriptase
polymerase chain reaction (PCR) in analogy to our previous studies
(45). The following customized primers were used for PCR
(Integrated DNA Technologies, Coralville, IA): 1) 5'-ATG TAC
AGG ATG CAA CTC CTG TCT TGC-3' and 5'-AGT CAG TGT TGA GAT GAT GCT TTG
ACA-3' for human IL-2 (GenBank accession number X01586); 2)
5'-ATG GAT TCA TAC CTG CTG ATG TGG GGA-3' and 5'-CTA GAT TGT TCT TCT
ACT CTT CCT CTG-3' for human IL-2R
(GenBank accession number
XM043150); 3) 5'-TGA CGC CCA ATG GGA ATG AAG ACA CCA-3' and
5'-TCT TCA GGG TGG GAA TTC GGG GCA TCG-3' for human IL-2R
(GenBank
accession number AH002843); and 4) 5'-ACC ACA GTC CAT GCC
ATC ACT GCC ACC-3' and 5'-TCC ACC ACC CTG TTG CTG TAG CCA AAT-3' for
human G3PDH (2). Equal volumes (10 µl) of PCR product
from each sample were separated on 1.5% agarose gel, stained with
ethidium bromide, and analyzed with the Kodak EDAS 290 documentation and analysis system (Rochester, NY). Only values from within the exponential phase of PCR amplification (typically <48 PCR cycles) were
considered for data analysis.
Reporter gene constructs.
The following constructs were used to model effects of biotin on
5'-flanking regions of genes encoding IL-2 and IL-2R. 1) A construct of the regulatory region of the IL-2 gene (spanning 321 bases upstream of the transcription start site) linked to the
luciferase gene [denoted p(-321)IL2-Luc] was provided by L. P. Freedman (Memorial Sloan-Kettering Cancer Center, New York, NY; Ref.
1). The regulatory elements of the IL-2 gene are located within ~300 bases upstream of the transcription start site (11, 16). 2) A construct of the regulatory region of the
IL-2R
gene (spanning 600 bases upstream of the transcription start
site) linked to the luciferase gene (denoted pPB
600) was provided by H. Asao (Tohoku University School of Medicine, Sendai, Japan; Ref.
27). The regulatory elements of the IL-2R
gene
are located within 600 bases upstream of the start site
(27). 3) A construct of the RSV promoter linked
to
-galactosidase gene (denoted RSV
gal) was used as control for
transfection efficiency (provided by B. R. White, University of
Nebraska-Lincoln, Lincoln, NE).
Western blots.
Effects of biotin supply on abundance of the receptor proteins IL-2R
and IL-2R
were investigated with Western blot analysis. Cellular
proteins (from 7.5 × 106 cells) were extracted with
detergent as described previously (13); protein
concentrations in extracts were quantified by bicinchoninic acid assay
(Pierce, Rockford, IL), and equal amounts of protein (up to 100 µg)
were loaded per lane for gel electrophoresis. Samples were
electrophoresed, electroblotted, and probed with antibodies to IL-2
receptors in analogy to our previous studies (13) with the
following minor modifications. Samples were electrophoresed with 4%
Tris-glycine gels (Invitrogen, Carlsbad, CA). IL-2R
and IL-2R
were probed with mouse anti-human antibodies clones 24204.11 and
38024.11, respectively (R&D Systems, Minneapolis, MN); stock solutions
(500 µg/ml) of these antibodies were diluted 250-fold before use.
Goat anti-mouse IgG peroxidase conjugate (Sigma, St. Louis, MO) was
used as secondary antibody; the stock solution (7.5 mg/ml) of this
antibody was diluted 50,000-fold before use. Antibody binding to
receptors was visualized by chemiluminescence (SuperSignal
chemiluminescent substrate; Pierce) as described previously
(13).
Endocytosis of 125I-labeled IL-2. Radiolabeled IL-2 was used to determine whether biotin supply affects receptor-mediated endocytosis of IL-2. Two micrograms of recombinant human IL-2 (Biosource; lot. no. L122602B) were radiolabeled with 125I with a commercial kit according to the manufacturer's instructions (Iodo-Beads; Pierce). Bovine serum albumin was added after iodination (5 g/l final concentration) to prevent adsorption of IL-2 to plastic surfaces. Unbound 125I was removed by gel exclusion chromatography (D-Salt desalting column; Pierce). Specific radioactivity of the final product was ~11.5 GBq/mmol.
Endocytosis of 125I-IL-2 was measured in analogy to previous reports (38, 42). Briefly, 10 × 106 Jurkat cells were stimulated with 50 µg/l of PMA and 2 mg/l of PHA in a volume of 2.6 ml for 17 h to induce synthesis of IL-2R. Cells were washed with phosphate-buffered saline to remove secreted IL-2 and were incubated with 10 nM 125I-IL-2 at 4°C for 1 h in a volume of 1 ml; incubation was continued at 37°C for 10 min. Cells were pelleted by centrifugation (500 g for 3 min) and washed three times with 1 ml of phosphate-buffered saline (4°C). Cells were resuspended in a small volume of water, and 125I-IL-2 was quantified in a gamma counter.Overexpression of IL-2R.
Biotin deficiency causes decreased expression of IL-2R
, leading to
decreased endocytosis (and increased extracellular concentrations) of
IL-2. Here we tested the hypothesis that overexpression of IL-2R
abolishes the effects of biotin supply on extracellular levels of IL-2
by using an expression vector. With total RNA from Jurkat cells as
template, cDNA was produced as described previously (45).
PCR primers were designed to add SacI/KpnI
restriction sites to the coding sequence of IL-2R
(GenBank accession
number D11086): 5'-ACT GAG CTC ATG TTG AAG CCA TCA TTA
CCA-3' and 5'-AGA GGT ACC TCA GGT TTC AGG CTT TAG
GGT-3' (Integrated DNA Technologies). The PCR product
(spanning the full coding sequence of IL-2R
) was cloned with the
AdvanTAge PCR cloning kit and the pT-Adv vector (Clontech, Palo Alto,
CA). The IL-2R
insert was sequenced five times at the DNA sequencing
core facility at the University of Nebraska-Lincoln; the sequence was
identical to the published sequence with the following exception. An
A-to-G substitution was found in position 332 compared with the
published sequence; the base triplets in both the published sequence
(CTA) and our clone (CTG) encode the same amino acid (leucine),
suggesting the existence of a silent variation in the IL-2R
gene.
Statistics. Homogeneity of variances among groups was tested with Bartlett's test (32). Variances were homogeneous; therefore, data were not transformed before further statistical testing. Significance of differences among groups was tested by one-way ANOVA. Fisher's protected least significant difference procedure was used for post hoc testing (32). StatView 5.0.1 (SAS Institute; Cary, NC) was used to perform all calculations. Differences were considered significant if P < 0.05. Data are expressed as means ± SD of separate experiments.
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RESULTS |
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Propionyl-CoA carboxylase.
Intracellular concentrations of biotin correlated with biotin
concentrations in culture media, as judged by activities of PCC. When
cells were cultured in biotin-deficient medium for 5 wk, activity of
PCC was 0.7 ± 0.6 pmol bicarbonate
fixed · 106
cells1 · min
1
compared with 6.4 ± 0.9 pmol bicarbonate
fixed · 106
cells
1 · min
1 in
cells that were cultured in medium containing a physiological concentration of biotin; activity of PCC was 34 ± 4.3 pmol
bicarbonate fixed · 106
cells
1 · min
1 when
cells were cultured in medium containing a pharmacological concentration of biotin (P < 0.05; n = 3 experiments).
Secretion of IL-2 and expression of IL-2 gene.
When cells were cultured in biotin-defined media for 5 wk,
concentrations of free extracellular IL-2 (in kU
IL-2 · l1 · 106
cells
1 over 6 h) correlated negatively with biotin
supply in response to stimulation with PMA and PHA: cells cultured in
deficient medium, 4.1 ± 0.3; cells cultured in physiological
medium, 3.0 ± 0.2; cells cultured in pharmacological medium,
1.8 ± 0.1 (P < 0.01; n = 5 experiments). This is consistent with previous observations (21,
43) and with the hypothesis that apparent secretion of IL-2
increases in response to biotin deficiency.
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Expression of genes encoding IL-2R and IL-2R
.
Expression of the IL-2R
gene correlated positively with biotin
concentrations in culture media. Both IL-2R
mRNA and IL-2R
protein were barely detectable in biotin-deficient cells and reached maximal levels in cells that were cultured in medium containing a
pharmacological concentration of biotin (Fig.
2). In contrast, expression of IL-2R
was not affected by biotin supply. Abundance of mRNA encoding the
housekeeping gene G3PDH (control) was similar among treatment groups.
These data are consistent with the hypothesis that biotin plays an
important role in the expression of IL-2R
in lymphoid cells.
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Overexpression of IL-2R.
Overexpression of IL-2R
by transfection with CMV-IL-2R
abolished
the effects of biotin on extracellular accumulation (apparent secretion) of IL-2 in Jurkat cells. In plasmid CMV-IL-2R
, expression of IL-2R
is under control of the cytomegalovirus (CMV) promoter, leading to constitutive expression of IL-2R
. Cells were cultured in
biotin-defined media, transfected with CMV-IL-2R
, and stimulated with PMA and PHA as described in Fig. 5.
Transfection with CMV-IL-2R
caused strong expression of IL-2R
in
all treatment groups, as judged by Western blot analysis with an
antibody to IL-2R
(Fig. 5A). Extracellular accumulation
of IL-2 was not affected by biotin supply in CMV-IL-2R
-transfected
cells (Fig. 5B), unlike in nontransfected cells (see above).
In fact, in contrast to nontransfected cells, we observed a moderate
decrease of extracellular IL-2 in biotin-deficient cells. This was
probably caused by the moderately greater abundance of IL-2R
protein
in CMV-IL-2R
-transfected, biotin-deficient cells compared with the
other treatment groups (Fig. 5A).
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DISCUSSION |
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The present study provides evidence that 1) biotin
supply affects expression of genes encoding IL-2 and IL-2R and
2) biotin-induced expression of IL-2R
causes increased
receptor-mediated endocytosis (i.e., decreased apparent secretion) of
IL-2 in lymphoid cells. These effects of biotin are probably not
specific for a given lymphoid cell line such as the Jurkat cells used
here; biotin supplementation also caused decreased apparent secretion
of IL-2 in previous studies in freshly isolated human lymphocytes
(43).
The present study and previous studies (21, 43) are
consistent with the hypothesis that biotin supplementation will benefit the immune system by the following two mechanisms. 1)
Biotin-supplemented cells produce more IL-2 than biotin-deficient cells
(as judged by abundance of mRNA), potentially leading to increased
growth and differentiation of T cells, natural killer cells and B
cells, and some myeloid cells (17). Consistent with this
hypothesis, proliferation rates increased transiently in
biotin-supplemented Jurkat cells compared with controls that were
cultured in medium containing a physiological concentration of biotin
(21). 2) Synthesis of IL-2R correlates with
biotin concentrations in human lymphoid cells. Effects of biotin on the
expression of the IL-2R
gene are likely to be beneficial because
IL-2R
plays a role not only in endocytosis of IL-2 (leading to
degradation of IL-2) but also in triggering intracellular signaling
pathways leading to growth and differentiation of immune cells in
response to IL-2 (17, 31, 37). Only those IL-2R
(heteromers) that contain IL-2R
can mediate IL-2-signaling:
high-affinity and intermediate-affinity receptors (37,
39). This is consistent with an essential role for IL-2R
in
signal transduction and in the human immune response. Mutations of the
gene encoding IL-2R
(as seen in human X-linked severe combined
immunodeficiency) are fatal if not cured by bone marrow
transplantation, consistent with a pivotal role for IL-2R
in the
immune system (37). IL-2R
is also assembled into
receptor heteromers for IL-4, -7, -9, and -15, underlining the
physiological importance of this receptor (17, 37). The
present study offers an explanation for the following paradox observed
in previous studies: biotin supplementation causes decreased apparent
secretion of IL-2 (21, 43) despite the fact that biotin
plays an essential role in the immune response (3, 7, 18,
28-30). The possibility that biotin increases the binding
affinity of IL-2 to its receptor(s) cannot be excluded on the basis of
the data presented here.
The observed effects on receptor-mediated endocytosis of IL-2 are
caused specifically by biotin rather than by a global increase in
transcriptional activity in response to cellular nutrient supply, on
the basis of the following lines of reasoning. 1) Biotin did not affect expression of genes encoding IL-2R and G3PDH, consistent with the hypothesis that biotin does not globally increase
transcriptional activity. 2) Transcriptional activity of
genes encoding IL-2 and IL-2R
did not increase in response to
supplementation with the vitamin riboflavin compared with
riboflavin-deficient cells (unpublished observation). This is
consistent with the hypothesis that transcription of the genes encoding
IL-2 and IL-2R
responds specifically to biotin.
There is precedence for the effects of biotin on gene expression. For
example, biotin affects transcription of genes encoding glucokinase,
phosphoenolpyruvate carboxykinase, and ornithine transcarbamylase
(4, 6, 8-10, 20, 34). The following models might
explain how biotin affects gene expression. 1) An intermediate of biotin metabolism, biotinyl-AMP, activates soluble guanylate cyclase, leading to increased production of cGMP
(33). cGMP stimulates protein kinase G (33),
leading to phosphorylation of enzymes and other proteins that regulate
processes such as transcription. 2) Histones (DNA-binding
proteins) in human lymphocytes are modified by covalent attachment of
biotin (35). Various covalent modifications of histones
may lead to increased transcriptional activity of genes
(40) such as IL-2 (5). Consistent with these
observations, biotinylation of histones correlates with increased
proliferation of human lymphocytes (35), a process that
depends on IL-2. 3) Biotin may bind to transcription factors that affect expression of genes encoding IL-2 and IL-2R. The identity of these transcription factors is currently unknown.
In the present study PCC activity was used as a marker for intracellular concentrations of biotin. Previous studies provided evidence that PCC activity is an early and sensitive marker for biotin status in rats (24); biotinylation of PCC (abundance of holo-PCC) correlates with concentrations of intracellular free biotin in rat livers (19). Likewise, biotinylation of PCC and other carboxylases in Jurkat cells correlates with biotin supply in culture media (21). Together, these studies are consistent with the hypothesis that activities of PCC in mammalian cells correlate with intracellular concentrations of free biotin, biotinylation of carboxylases, and cellular biotin supply.
The effects of nutrient status on immune function were investigated in numerous previous studies. These studies frequently used secretion of cytokines by immune cells as a marker to model effects of nutrient deficiency or supplementation on immune function. The present study suggests that the approach of quantifying apparent secretion of cytokines without quantifying cytokine receptors may be too simplistic. Previous studies that relied solely on the analysis of extracellular cytokine levels may require careful reevaluation.
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ACKNOWLEDGEMENTS |
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We thank Drs. H. Asao (Tohoku University School of Medicine), L. P. Freedman (Memorial Sloan-Kettering Cancer Center), and B. R. White (University of Nebraska-Lincoln) for generously providing plasmids for these studies.
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FOOTNOTES |
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-60447 and U.S. Department of Agriculture/National Research Initiative Competitive Grants Program Project Award 2001-35200-10187. This article is a contribution by the University of Nebraska Agricultural Research Division, Lincoln, NE 68583 (Journal Series No. 13792).
Address for reprint requests and other correspondence: J. Zempleni, Dept. of Nutritional Sciences and Dietetics, Univ. of Nebraska at Lincoln, 316 Ruth Leverton Hall, Lincoln, NE 68583-0806 (E-mail: jzempleni2{at}unl.edu).
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. Section 1734 solely to indicate this fact.
First published October 16, 2002;10.1152/ajpcell.00365.2002
Received 23 September 2002; accepted in final form 7 October 2002.
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