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Vol. 289, Issue 2, 649-655, May 1999
Institut National de la Santé et de la Recherche Médicale U481 and Centre de Recherche de l'Association Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France
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Abstract |
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 Top
 Abstract
 Introduction
Experimental Procedures
Results
Discussion
References
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The interaction of interleukin-2 (IL-2) with its receptor (IL-2R) decreases cytochrome P-450 (CYP) expression in rat hepatocytes. Because IL-2 increases c-Myc in lymphocytes and because c-myc overexpression represses several genes, we postulated that the IL-2/IL-2R interaction may increase c-Myc and thereby down-regulate CYP in hepatocytes. Cultured rat hepatocytes were exposed for 24 h to IL-2 (350 U/ml) and other agents. IL-2 increased c-myc mRNA and protein but decreased total CYP and the mRNAs and proteins of CYP2C11 and CYP3A. The IL-2-mediated c-myc overexpression and CYP down-regulation were prevented by 1) genistein (a tyrosine kinase inhibitor that blocks the initial transduction of the IL-2R signal), 2) retinoic acid, butyric acid, or dimethyl sulfoxide (three agents that block c-myc transcription), or 3) an antisense c-myc oligonucleotide (which may cause rapid degradation of the c-myc transcript). It is concluded that IL-2 causes the overexpression of c-myc and the down-regulation of CYPs in rat hepatocytes. Block of c-myc overexpression, at three different levels with five different agents, prevents CYP down-regulation, suggesting that c-myc overexpression may directly or indirectly repress CYP in hepatocytes.
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Introduction |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Interleukin-2
(IL-2) plays a pivotal role in immunological responses (Waldmann,
1993
). When the T cell receptor of a helper T lymphocyte recognizes a
foreign peptide on the surface of an antigen-presenting cell, the
expression of IL-2 and that of its receptor (IL-2R) are induced in this
helper T cell (Waldmann, 1993). The IL-2R is an heterotrimer of
IL-2R
, 
, and 
subunits (Waldmann, 1993; Nelson et al., 1994).
The chain increases the receptor affinity for IL-2, and stabilizes
interactions among IL2R, IL-2, and IL2R (Nelson et al., 1994).
The binding of IL-2 between the extracellular segments of IL-2R and
IL-2R induces the heterodimerization of their cytoplasmic domains
and mediates the signal for T cell proliferation and differentiation
(Nelson et al., 1994). The signal starts with the activation of several tyrosine kinases (Nelson et al., 1994), which can be blocked with genistein, a tyrosine kinase inhibitor (Nishio et al., 1994). The
IL-2/IL-2R interaction also activates natural killer lymphocytes that
can lyze tumor cells (Trinchieri, 1989). Accordingly, IL-2 is used in
the treatment of some cancers (Lotze et al., 1985). However, high i.v.
doses are required, causing high serum IL-2 levels (4000 U/ml at 10 min) and a variety of toxic effects (Lotze et al., 1985).
Several other cytokines, including interferons, tumor necrosis
factor-, IL-1, and IL-6, repress the transcription of cytochrome P-450 (CYP) genes in cultured human or rat hepatocytes (Abdel-Razzak et
al., 1993; Chen et al., 1995), and interferon administration decreases
hepatic drug metabolism in rats and humans (Craig et al., 1993).
Similarly, the administration of human recombinant IL-2 decreases the
expression of CYPs in rats (Thal et al., 1994). The IL-2R is expressed
on the surface of rat hepatocytes, and IL-2 down-regulates the
expression of CYPs in primary cultures of rat hepatocytes (Tinel et
al., 1995). This effect is not caused by increased NO formation since
medium nitrites are unchanged in IL-2-treated hepatocytes (Tinel et
al., 1995). CYP down-regulation is blocked either by a monoclonal
antibody against the IL-2R or by genistein, indicating that CYP
down-regulation is mediated by the IL-2R (Tinel et al., 1995). However,
the ultimate signal or signals involved in the down-regulation of CYPs
were not determined (Tinel et al., 1995).
In lymphocytes, the activation of Src-type tyrosine kinases by the
IL-2R is accompanied by the induction of the c-fos and c-jun genes, whereas the activation of the Janus kinase
family is associated with c-myc activation (Asao et al.,
1994). c-Myc exerts opposite transcriptional effects in different
genes. Myc/Max heterodimers act as activators of transcription for the
genes that exhibit the CACGTG consensus DNA sequence (E box
myc site) in their upstream promoter region, whereas in
contrast, c-myc overexpression directly or indirectly
inhibits the transcription of many other genes that do not contain E
box myc sites (Roy et al., 1993; Li et al., 1994; Antonson
et al., 1995; Mink et al., 1996).
We therefore postulated that the IL-2/IL-2R interaction may overexpress
c-myc and thereby down-regulate CYPs in hepatocytes. In the
present study, we show that IL-2 increases c-myc expression and down-regulates CYPs in cultured rat hepatocytes. Prevention of
c-myc overexpression at different steps always prevented CYP down-regulation. Indeed, 1) genistein, which blocks the initial IL-2R
signal transduction (Nishio et al., 1994; Tinel et al., 1995); 2)
retinoic acid, butyric acid, or DMSO, three agents that decrease
transcription of the c-myc gene (Westin et al., 1982; Dony
et al., 1985; Krumm et al., 1992; Strobl and Eick, 1992; Heruth et al.,
1993); and 3) an antisense c-myc phosphorothioate oligodeoxynucleotide [P(S)ODN], which may cause the rapid breakdown of the c-myc transcript (Scanlon et al., 1995), prevented
the overexpression of c-myc in IL-2-treated cells and
concomitantly prevented IL-2-mediated CYP down-regulation.
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Experimental Procedures |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Animals and Materials. Male Sprague-Dawley CDCrl:CD (SD)BR rats were purchased from Charles River (Cléon, France). Animals were fed with a normal standard diet (Autoclavé 113; Usine d'Alimentation Rationnelle, Villemoisson-sur-Orge, France) and used when they weighed 180 to 190 g.
Human recombinant IL-2 was purchased from Genzyme (Cambridge, MA). n-Butyric acid, DMSO, retinoic acid, genistein, and erythromycin were from Sigma Chemical Co. (St. Louis, MO). Collagenase type I and the transfection reagent N-[1-(2,3-dioleoyloxy)propyl)]-N,N,N-trimethylammonium methylsulfate (DOTAP) were obtained from Boehringer-Mannheim (Mannheim, Germany). Collagen-coated culture dishes were from Polylabo (Strasbourg, France). [32P]Deoxycytidine triphosphate (3000 Ci/mmol) and enhanced chemiluminescence (ECL) kits were from Amersham (Les Ulis, France). Protein A-Sepharose was from Pharmacia (Uppsala, Sweden). Peroxidase-conjugated streptavidin was from DAKO (Glostrup, Denmark).Anti-c-Myc Antibodies, c-myc DNA Probes, and c-myc P(S)ODNs. A mouse monoclonal anti-c-Myc antibody and a rabbit polyclonal anti-c-Myc antibody were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). These two antibodies were used to immunoprecipitate and reveal c-Myc, respectively.
A cDNA probe covering the region from nucleotides 71 to 1053 of the human glyceraldehyde-3-phosphate dehydrogenase (G3PDH) gene was purchased from Clontech (Palo Alto, CA). The ClaI/EcoRI 1.4-kb probe for the c-myc third exon was purchased from Appligene Oncor (Illkirch, France). Antisense (5'-CACGTTGAGGGGCAT-3') and sense (5'-ATGCCCCTCAACGTG-3') c-myc P(S)ODNs were prepared by Genset (Paris, France). These P(S)ODNs correspond to the sequence ranging from nucleotides 1995 to 2010 of rat c-myc (Hayashi et al., 1987). This is the
initial translation initiation region for the second exon, which is the
first to be translated because the first rat exon has no coding
capacity (Hayashi et al., 1987). Equivalent 15-mer ODNs for human
c-myc have been used in previous antisense studies (Holt et
al., 1988; Shi et al., 1992). This region was selected because it is
single-stranded in the human c-myc transcript (Holt et al.,
1988), and the rat and human genes differ by only one base in this region.
Anti-CYP Antibodies and CYP Primers.
The anti-CYP antibodies
used in this study and the primers used to assess the CYP2C11, CYP3A,
and -actin transcripts by reverse transcription (RT)-polymerase
chain reaction (PCR) have been described (Thal et al., 1994; Tinel et
al., 1995).
Cell Culture.
Hepatocytes were isolated by collagenase
perfusion as previously described (Tinel et al., 1995). The viability
of hepatocytes determined by trypan blue exclusion was greater than
85%. Isolated hepatocytes were cultured on collagen-coated culture
dishes in William's E medium supplemented with 0.1 mg/ml insulin
(Sigma), 100 U/ml penicillin, 0.1 mg/ml streptomycin, 70 µM
hydrocortisone, and 10% fetal calf serum (FCS). Hepatocytes were
maintained at 37°C in a humidified incubator under 5%
CO2 in air. After the attachment period (3 h),
the medium was removed and replaced by a fresh medium without FCS and
with or without IL-2 (350 U/ml). In preliminary experiments, this dose
of pure human recombinant IL-2 (Genzyme) was found to reproduce the CYP
effects that we had observed with 10-fold higher doses of the human
recombinant IL-2 that was mixed with a dextran vehicle (Roussel-Uclaf)
(Tinel et al., 1995), suggesting that this vehicle may inhibit the
binding of IL-2 with its receptor. In some culture dishes, genistein
(20 µg/ml), retinoic acid (10 µM), n-butyric acid (3 mM), or DMSO (2%) also was added. Measurements were made after 24 h of treatment. In other experiments, treatments were applied from 24 to 48 h after cell attachment, and CYPs were studied 48 h
after cell attachment.
Northern Blot Analysis of c-myc mRNA.
Total
RNAs were isolated from culture dishes as described previously (Tinel
et al., 1995). Total RNA (20 µg) was subjected to 1.2% agarose gel
electrophoresis in the presence of 6.6% formaldehyde, transferred by
capillarity to Hybond N+ nylon membranes
(Amersham), and baked for 2 h at 80°C. The c-myc and
G3PDH probes were labeled with [32P]dCTP by
random priming. The nylon membranes were prehybridized for 4 h in
50% formamide, 5× Denhardt's solution, 10% dextran sulfate, 6×
standard sodium citrate, 1% SDS, and 20 µg/ml salmon sperm DNA and
then hybridized for 24 h with the DNA probe (2 × 106
cpm/ml). After three washings, membranes were exposed to
autoradiography film (5 days at 
80°C), and RNA bands were
quantified by laser scanning.
Immunoprecipitation and Immunoblots of c-Myc Protein.
Hepatocytes (106 cells) were washed in PBS and
lyzed with 0.1% Nonidet P-40 (BDH Laboratory Supplies, Poole,
England), 250 mM NaCl, 5 mM EDTA, 1 mM phenylmethylsulfonyl fluoride,
0.5 mM sodium orthovanadate, 5 mM sodium fluoride, and 50 mM HEPES
buffer, pH 7.8 (Robin et al., 1996). After protein measurement, the
cell lysate was diluted to a protein concentration of 0.2 mg/ml, as described previously (Robin et al., 1996). Then, 1 ml was incubated with the anti-c-Myc mouse monoclonal antibody (2 µg) for 1 h at room temperature.
). After incubation with the
blocking reagent (Amersham), nitrocellulose sheets were incubated for
1 h with the anti-c-Myc rabbit polyclonal antibody (diluted 1:3000
in Tween-20, Tris-buffered saline, pH 7.6). Sheets were then incubated
for 1 h with a horseradish peroxidase-linked antibody raised in
donkeys against rabbit immunoglobulins (Amersham) diluted 1:1500.
Immunoreactive c-Myc was revealed by an ECL detection system
(Amersham). Quantification of the protein bands was performed by laser densitometry.
Cellular CYP, Erythromycin Demethylation, and CYP Proteins.
Total cellular CYP was measured by the CO-difference spectrum of
dithionite-reduced cell lysates as described previously (Tinel et al.,
1995). Cell erythromycin N-demethylation, an activity supported by CYPs 3A, was measured with a whole-cell homogenate as
described previously (Tinel et al., 1995).
). The cell pellet was resuspended in
0.1 M phosphate buffer, pH 7.4, and sonicated with a 80-W Vibracell
sonicator (Bioblock, Illkirch, France). The microsomes were isolated by
differential centrifugation at 10,000g and then 100,000g, and resuspended in 0.1 M phosphate buffer, pH 7.4, 1 mM EDTA, and 20% of glycerol. The microsomal suspension was kept at
80°C until use.
Unless otherwise indicated, 10 µg of microsomal proteins was
fractionated by SDS-10% PAGE as described previously (Tinel et al.,
1995). Electrophoretic transfer to nitrocellulose sheets was performed
in a Bio-Rad semidry transfer cell (Bio-Rad, Ivry-sur-Seine, France).
Unspecific binding sites were blocked with 1% Tween-20 and 1%
polyvinylpyrrolidone in PBS, pH 7.2. Nitrocellulose sheets were first
incubated with the anti-CYP sera diluted 1:1000 (anti-CYP1A and
anti-CYP3A), 1:500 (anti-CYP2C11), or 1:100 (anti-CYP2B and anti-CYP2D1) in PBS containing 10% BSA and 10% neonatal calf serum and then incubated with the peroxidase-conjugated antibody against rabbit or mouse immunoglobulins (DAKO, Copenhagen, Denmark) and stained
with diaminobenzidine and
H2O2 in the presence of
0.015% CoCl2 and 0.015%
NiCl2. In experiments performed with the sense or
antisense P(S)ODN, immunoblots (1.5 µg of microsomal proteins) were
revealed with an ECL system (Amersham). Protein bands were quantified
by laser densitometry. The linearity of densitometric measurements was
verified in preliminary experiments.
CYP2C11 and CYP3A mRNAs.
The transcripts of CYP2C11, CYP3A,
and -actin were assessed by RT-PCR as described previously (Tinel et
al., 1995). Briefly, cDNAs were synthesized from 1 µg of total RNA
using the Moloney murine leukemia virus RT system, followed by PCR
amplification in the presence of the corresponding primers and
[32P]deoxycitidine triphosphate (1 µCi/tube)
as described previously (Tinel et al., 1995). After 1.5% agarose gel
electrophoresis, the amplified cDNA bands were excised under UV light
and counted for 32P radioactivity (Tinel et al.,
1995).
Statistical Analysis. ANOVA followed by a Dunnett's t test was used to assess the significance of differences between mean values.
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Results |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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Prevention of IL-2-Mediated Increase in c-myc mRNA
and Decrease in CYP by Retinoic Acid, n-Butyric Acid, or
DMSO.
Because IL-2 has been shown to increase c-myc
expression in lymphocytes (Asao et al., 1994), we looked for similar
effects in hepatocytes (Fig. 1). The
c-myc mRNA was increased by 140% in hepatocytes cultured
for 24 h with IL-2 (350 U/ml) (Fig. 1). Retinoic acid,
n-butyric acid, and DMSO, three agents that have been shown
to decrease transcription of the c-myc gene (Westin et al.,
1982; Dony et al., 1985; Krumm et al., 1992; Strobl and Eick, 1992;
Heruth et al., 1993), all prevented the IL-2-mediated increase in
c-myc mRNA in IL-2-treated cells (Fig. 1). When added alone
(without IL-2), these agents had limited effects on c-myc mRNA, which was not significantly decreased compared with control cells
(Fig. 1).
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Prevention by Genistein.
In lymphocytes or hepatocytes, the
IL-2/IL-2R signal starts with the activation of tyrosine kinases, which
are inhibited by genistein (Nishio et al., 1994; Tinel et al., 1995).
Genistein (20 µg/ml) prevented the IL-2-mediated increase in
c-myc mRNA and decrease in total CYP in IL-2-treated cells,
although genistein alone had no significant effects on c-myc
mRNA or CYP (Fig. 3).
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Prevention by an Antisense c-myc P(S)ODN.
A
frequent mechanism of action of antisense ODNs is the rapid breakdown
of the transcript due to the degradation of the mRNA/DNA duplex by cell
RNase H (Scanlon et al., 1995). A c-myc antisense P(S)ODN
markedly decreased c-myc mRNA in IL-2-treated cells (Fig. 4 and Table
2). Changes in c-Myc protein were about
half the changes in c-myc mRNA (Fig. 4 and Table 2). IL-2
increased c-myc mRNA by 114%, although it increased c-Myc
protein by 49%; the antisense P(S)ODN decreased c-myc mRNA
by 71% in IL-2-treated cells, whereas this antisense caused a 42%
decrease in c-Myc protein in these cells (Fig. 4 and Table 2). Thus,
the antisense P(S)ODN just normalized the c-Myc protein in IL-2-treated
cells, leaving residual levels that were not significantly lower than
those in control cells (Fig. 4 and Table 2).
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Discussion |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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It has been shown previously that the IL-2R is expressed by rat
hepatocytes and that the IL-2/IL-2R interaction down-regulates the
expression of CYPs in these cells (Tinel et al., 1995). However, the
ultimate signal or signals involved in the down-regulation of CYPs have
not been determined (Tinel et al., 1995).
In the present study, we show that the IL-2/IL-2R interaction causes
the overexpression of c-myc mRNA and c-Myc protein in rat
hepatocytes (Fig. 4 and Table 2). Three different pieces of evidence
support a major role of c-myc overexpression in the IL-2-mediated CYP down-regulation. First, genistein, a tyrosine kinase
inhibitor that blocks the initial IL-2R signal transduction (Nishio et
al., 1994; Tinel et al., 1995), prevented the IL-2-mediated overexpression of c-myc mRNA and down-regulation of CYP
(Fig. 3). Second, three agents (retinoic acid, n-butyric
acid, and DMSO) that block c-myc transcription (Westin et
al., 1982; Dony et al., 1985; Krumm et al., 1992; Strobl and Eick,
1992; Heruth et al., 1993) prevented the IL-2-mediated overexpression
of c-myc mRNA and down-regulation of CYP (Figs. 1 and 2 and
Table 1). Finally, an antisense
c-myc P(S)ODN that may cause the rapid breakdown of the
c-myc transcript due to the degradation of the mRNA/DNA duplex by cell RNase H (Scanlon et al., 1995) prevented the
IL-2-mediated increase in c-myc mRNA and c-Myc protein and
totally or mostly prevented the IL-2-mediated decreases in total CYP,
CYP mRNAs, and CYP proteins (Fig. 4 and Table
2). Thus, prevention of the IL-2-mediated
c-myc overexpression by five different agents, acting at
three different levels (signal transduction, c-myc
transcription, c-myc mRNA stability), always prevented CYP
down-regulation, suggesting a major role of c-myc
overexpression in IL-2-mediated CYP down-regulation.
In cells treated with IL-2 and either retinoic acid, n-butyric acid, DMSO or the c-myc antisense P(S)ODN, none of the CYP proteins were statistically different from values in untreated cells (Tables 1 and 2). However, although the mean values for CYP1A1, CYP1A2, CYP2B1/2, CYP2D1, or CYP3A ranged from 81% to 141% of control values in these protected cells, CYP2C11 values tended to remain slightly low, at 74%, 82%, 99%, and 74% of control values in cells protected by retinoic acid, n-butyric acid, DMSO, or the c-myc antisense P(S)ODN, respectively (Tables 1 and 2). Thus, we cannot exclude that in addition to the major role of c-myc overexpression suggested by the present study, some other signal or signals may be also involved in the IL-2-mediated down-regulation of some particular CYPs, including CYP2C11.
In previous studies, c-Myc has been shown to repress the transcription
of several genes, including those of major histocompatibility complex
class I molecules, albumin, leukocyte function antigen-1, neural
cell adhesion molecule, the adenovirus-2 major late promoter, and the
CCATT/enhancer binding protein (C/EBP) (Roy et al., 1993; Li et
al., 1994; Antonson et al., 1995). Because several of these genes
contain a TCA(+1) transcription initiator element (Inr), it has been
initially suggested that Myc (alone or in combination with other
factors) may interact with the Inr sequence to repress transcription
(Li et al., 1994). However, it was shown later that mutation of the Inr
site did not abolish these effects, suggesting that Myc may instead (or
also) interact with other component or components of the basal
transcription machinery (Antonson et al., 1995).
In addition to these direct effects, Myc may act indirectly, by
inhibiting C/EBP-dependent transactivation (Mink et al., 1996). Myc has
two effects on C/EBPs (Mink et al., 1996). First, it suppresses C/EBP and C/EBP mRNA levels (Mink et al., 1996). Second, Myc suppresses C/EBP-mediated transactivation even when the amount of the
C/EBP transcription factors remains constant (e.g., in cells
transfected with a constitutively active C/EBP expression vector)
(Mink et al., 1996). C/EBPs are important transcription factors in
hepatocytes, and the 5'-flanking region of most CYPs, including those
investigated in the present study, contains possible C/EBP-binding
sequences. Indeed, C/EBP-responsive elements have been recently
implicated in the regulated expression of CYPs3A (Ourlin et al., 1996),
CYP2B1 and CYP2B2 (Luc et al., 1996), or CYP2C11 and CYP2C12 (Buggs et
al., 1998).
Interestingly, the direct or indirect role of c-myc
overexpression in CYP repression may also apply to several other
conditions. First, ongoing studies in our laboratory show that the
interaction of epidermal growth factor with its receptor also increases
c-myc expression and decreases CYP in rat hepatocytes. These
effects are prevented by genistein, retinoic acid, and DMSO. Second,
several other cytokines, including IL-1, IL-6, tumor necrosis
factor-, and interferons, cause both c-myc overexpression
in lymphocytes (Kovacs et al., 1986; Lomo et al., 1991; Escriou et al.,
1992; Chaouchi et al., 1994; Georgakopoulos et al., 1996) and CYP
down-regulation in hepatocytes (Abdel-Razzak et al., 1993; Chen et al.,
1995). Finally, overexpression of c-myc, down-regulation of
C/EBP, and down-regulation of CYPs occur in neoplastic hepatocytes
(Wiebel et al., 1984; Fujiwara et al., 1993; Habib et al., 1994, Jover et al., 1998) or the regenerating rat liver (Liddle et al., 1989; Mischoulon et al., 1992; Habib et al., 1994). Conceivably, the c-myc-induced down-regulation of CYPs in dividing
hepatocytes may offer a survival advantage by decreasing the formation
of DNA-damaging electrophilic metabolites during the critical period of
DNA replication. Interestingly, forced reexpression of C/EBP (through stable transfection with a C/EBP vector containing a zinc-inducible metallothionein promoter) was shown to up-regulate several CYP mRNAs in HepG2 cells (Jover et al., 1998). This observation strengthens the view that c-myc overexpression may
down-regulate CYP expression by first down-regulating C/EBP expression.
IL-2 immunotherapy is used in patients with disseminated cancer (Lotze
et al., 1985). However, high IL-2 doses are required, causing high
serum IL-2 concentrations (4000 U/ml) (Lotze et al., 1985). In the
present study, 350U/ml IL-2 caused significant CYP down-regulation in
rat hepatocytes (Table 1). Thus, human IL-2 concentrations may be
sufficiently high to cause CYP down-regulation. Indeed, IL-2
immunotherapy decreased hepatic CYP proteins and monooxygenase
activities in patients with cancer (Elkahwaji et al., 1999), suggesting
the possibility of drug interactions.
In conclusion, the IL-2/IL-2R interaction causes c-myc
overexpression and CYP down-regulation in cultured rat hepatocytes. CYP
down-regulation is prevented by five different agents that prevent
c-myc overexpression at three different levels (initial IL-2
signal transduction, c-myc transcription, c-myc
mRNA stability), suggesting a major role of c-myc
overexpression in IL-2-mediated CYP down-regulation. It remains to be
determined whether c-myc overexpression acts directly on CYP
expression and/or first inhibits the expression and transactivating
effects of C/EBP.
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Acknowledgments |
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We are grateful to Philippe Beaune (INSERM U490, Paris, France) for the generous gift of anti-CYP antibodies.
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Footnotes |
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Accepted for publication December 3, 1998.
Received for publication July 31, 1998.
1 This study was supported in part by The European Union Eurohepatox BIOMED 2 Program (contract BMH4-CT96-0658), the Program Hospitalier de recherche Clinique 95-96, and the Réseau Hépatox.
Send reprint requests to: Dr. Dominique Pessayre, M.D., INSERM U481, Hôpital Beaujon, 92118 Clichy, France. E-mail pessayre{at}bichat.inserm.fr
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Abbreviations |
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IL, interleukin; IL-2R, interleukin-2 receptor; CYP, cytochrome P-450; DMSO, dimethyl sulfoxide; P(S)ODN, phosphorothioate oligodeoxynucleotide; DOTAP, N-[1-(2,3-dioleoyloxy)propyl)]-N,N,N-trimethylammonium methylsulfate; ECL, enhanced chemiluminescence; RT, reverse transcription; PCR, polymerase chain reaction; C/EBP, CCAAT/enhancer binding protein.
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References |
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Top
Abstract
Introduction
Experimental Procedures
Results
Discussion
References
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26 (Suppl 2):
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