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J Virol, August 1998, p. 6917-6921, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Interleukin-12 p40 mRNA Expression in Bovine
Leukemia Virus-Infected Animals: Increase in Alymphocytosis but
Decrease in Persistent Lymphocytosis
Dohun
Pyeon and
Gary A.
Splitter*
Department of Animal Health and Biomedical
Sciences, University of Wisconsin
Madison, Madison, Wisconsin
53706
Received 16 March 1998/Accepted 4 May 1998
 |
ABSTRACT |
Interleukin-12 (IL-12), a key cytokine in immune regulation, has an
important role in activating the cell-mediated immune response
in infectious diseases. Recently, a dichotomy between IL-12 and IL-10
regarding progression of a variety diseases has emerged. IL-12
activates type 1 cytokine production and has an antagonistic effect on
type 2 cytokines. Here, by using quantitative competitive PCR, we show
that peripheral blood mononuclear cells from bovine leukemia
virus-infected animals in the alymphocytotic stage of disease express
an increased amount of IL-12 p40 mRNA. In contrast, IL-12 p40 mRNA
expression by cells from animals with late-stage disease, termed
persistent lymphocytosis, was significantly decreased compared to that
by normal and alymphocytotic animals. Interestingly, IL-12 p40 mRNA was
also detected in tumor-bearing animals. IL-12 p40 expression occurred
only in monocytes/macrophages, not B or T lymphocytes. The present
study combined with previous findings suggest that IL-12 in bovine
leukemia virus-infected animals may regulate production of other
cytokines such as gamma interferon and IL-10 and the progression of
bovine leukosis in animals that develop more advanced disease such as a
persistent lymphocytosis of B cells or B-cell lymphosarcoma.
| |
TEXT |
Bovine leukemia virus (BLV), closely
related to human T-cell leukemia virus type 1, is a type C retrovirus
infecting bovine B cells and leads to development of enzootic bovine
leukosis (20). Fewer than 5% of infected animals develop
malignant lymphosarcoma (12), while 30% of infected animals
progress to persistent lymphocytosis (PL animals), in which
nonneoplastic B cells proliferate and leukocyte counts may exceed
10,000/mm3 (22). However, most infected animals
remain in the alymphocytotic (AL) stage. Despite the often long
duration for disease transition, the mechanisms for progression are as
yet unknown. Previously, we determined that cytokine profiles of
BLV-infected animals differ depending on the stage of disease
(29). Type 1 cytokines, interleukin-2 (IL-2) and gamma
interferon (IFN-
), were expressed in high amounts in AL animals,
while the type 2 cytokine IL-10 increased in PL animals. This finding
suggests that the transition in cytokines may be a contributing factor
to disease progression. Cytokine imbalance may contribute to disease
progression in human immunodeficiency virus (HIV) infection as well as
autoimmune diseases and cancers (8, 33). To examine the
polarization of cytokine production in BLV infection, we tested the
quantity of IL-12 in animals in different stages of disease. IL-12 is a
heterodimer comprised of two unrelated chains, p40 and p35, and is
produced by several different types of cells, including dendritic
cells, macrophages, neutrophils, keratinocytes, Langerhans cells, and B
cells (23, 34). T cells, natural killer (NK) cells, and B
cells are affected by IL-12. IL-12 has proinflammatory and
immunoregulatory effects on T helper (Th) cell responses inducing
T-cell differentiation and optimal proliferation and cytokine
production in mature Th1 cells and inhibiting production of type 2 cytokines. Also, IL-12 can initiate development of Th1 cells because
only Th1 cells possess the IL-12 receptor 
2 subunit (30,
32). In this study, we demonstrate that IL-12 p40 quantitatively
increases in AL animals but significantly decreases in PL animals and
that monocytes/macrophages are the only detectable source of IL-12
production.
Determination of disease stage and IL-12 p40 production.
Adult
female Holstein cattle, 2 to 12 years of age, were assigned to three
groups according to their disease stage. Five normal, three AL, three
PL, and three tumor-bearing animals were used for reverse transcriptase
PCR (RT-PCR) of IL-12 p40 mRNA. Heparinized blood was obtained from the
jugular vein, and peripheral blood mononuclear cells (PBMCs) were
isolated by density gradient centrifugation (7).
BLV-infected animals were identified by enzyme-linked immunosorbent
assay by using sera of cattle with BLV antigen-coated microplates
(14). PL animals were distinguished by cell counts and
changes in B-cell numbers determined by flow cytometry. PL animals had
more than 5,500 PBMCs/mm3 and 55 to 80% B cells, while AL
and normal animals had 20 to 30% B cells (Table
1).
Cytoplasmic lysates from freshly isolated PBMCs were obtained by adding
200 µl of chloroform, and total RNA was prepared by
using TRI reagent
(MRC, Cincinnati, Ohio) as described in the
manufacturer's protocol.
Concentration of purified total RNA was
determined by
spectrophotometer. Total mRNA was isolated from
PBMCs of animals in
different disease stages by using magnetic
isolation. PCR was performed
in a DNA thermocycler (Perkin-Elmer,
Norwalk, Conn.) for 33 to 38 cycles consisting of 45 s at 94°C
for denaturation, 1 min at 60 or 62°C for annealing, and 1 min
at 72°C for polymerization. Each
PCR mixture contained 1.25 U
of
Taq polymerase, 1.5 mM
MgCl
2, 0.8 mM deoxynucleoside triphosphates,
1 µM
primers, template, and 10× thermobuffer (500 mM KCl, 100
mM Tris-HCl
[pH 9.0], 1% Triton X-100). Primers were designed
with Oligo 5.0 software (National Bioscience, Plymouth, Minn.)
and were based on
GenBank sequence information (Table
2).
Primers
for IL-12 p40 were based on the bovine IL-12 p40 cDNA sequence
(
37). To produce a plasmid containing IL-12 p40, PCR
products
from phytohemagglutinin (5 µg/ml; Sigma, St. Louis, Mo.)- or
concanavalin
A (10 µg/ml; Sigma)-stimulated PBMCs were cloned into
the TA cloning
vector pCR2.1 (Invitrogen, San Diego, Calif.) as
recommended by
the manufacturer. Plasmids were purified from
transformed
Escherichia coli by use of the Wizard miniprep
system (Promega, Madison, Wis.)
and then screened for an insert by
EcoRI digestion followed by
agarose gel electrophoresis.
Dideoxy sequencing of positive clones
was performed with T7 and
M13 sequencing primers followed by separation
on a Sequagel-6 6%
sequencing gel (National Diagnostics, Atlanta,
Ga.).
-Actin
(5'-ACCAACTGGGACATGGAG, 3'-GCATTTGCGGTGGACAATGGA;
890-bp product) (
11) and IL-12 p40
(5'-TGAGGCAAAGGATTATTCTG,
3'-AGATGCCCATTCACTCCAGA; 577-bp product) primers
(
37) were used
for amplification. Amplified products were
analyzed by 1% agarose
gel electrophoresis. Samples from RT
reaction mixtures without
Moloney murine leukemia virus RT and mixtures
without cDNA template
were used in PCR assays as controls for
amplification of contaminated
DNA fragments. IL-12 p40 mRNA expression
by animals in AL, PL,
and tumor-bearing stages was qualitatively
detected by RT-PCR.
The clear bands of IL-12 p40 were detected in
noncultured cells
from normal, AL, and tumor-bearing animals. In
contrast, only
a trace amount of IL-12 p40 was detected in
animals in the PL
stage of disease (Fig.
1).
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FIG. 1.
Representative bands of IL-12 p40 qualitatively
expressed by PBMCs of BLV-infected animals with different stages of
disease and of a normal (BLV ) animal. The IL-12 p40 band,
577 bp, was generated from total RNA by using RT-PCR. All products were
analyzed on a 1% agarose gel stained by ethidium bromide.
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|
Quantification of IL-12 p40.
To verify the precise differences
in IL-12 p40 levels produced by animals in different disease stages,
IL-12 p40 mRNA was quantified by using mimics. IL-12 p40 mimic (380 bp)
and -actin mimic (525 bp) were generated by nonspecific PCR
amplification. IL-12 p40 and -actin quantitation were optimized by
using different amounts of standard template plasmid and a fixed amount
of mimic plasmids in each tube (35). In -actin standard
reaction mixtures, serial twofold dilutions of standard templates from
410 fmol to 800 amol were amplified competitively with 1 fmol mimic
template (Fig. 2a and b). In the IL-12
standard reaction mixtures, serial twofold dilutions of the IL-12
templates from 26 fmol to 50 amol were amplified with 5 fmol mimic
template (Fig. 2c and d). On the basis of band ratios, a standard graph
was generated and r2 values of the standard
reaction mixture were more than 0.950, confirming that the amount of
total RNA paralleled the ratio of total RNA to IL-12 p40 mimic (data
not shown). Since the concentration of isolated mRNA was below the
limit of detection by spectrophotometry, the concentration of -actin
was measured for each animal and used as an internal control for IL-12
p40 mRNA production. Isolated mRNA was diluted at least 100 times for
-actin quantitation to compensate for the difference between
-actin and IL-12 p40 mRNA concentrations.
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FIG. 2.
Standard reaction of -actin (a and b) and IL-12 p40
(c and d). Standard (std) DNA, 410 fmol to 800 amol for -actin
(Act) and 26 fmol to 50 amol for IL-12 p40, was amplified with 1 or
5 fmol of mimic DNA for -actin or IL-12 p40, respectively. The
product sizes are as follows: standard -actin, 890 bp; mimic
-actin, 525 bp; standard IL-12 p40, 577 bp; mimic IL-12 p40, 380 bp.
All products were analyzed on a 1% agarose gel stained by ethidium
bromide. Band density was measured by densitometry by using the NIH
Image 1.59 program, and the standard graph was generated on the basis
of density ratios.
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|
Interestingly, expression of IL-12 p40 mRNA increased in AL animals but
decreased in PL animals relative to that in BLV-seronegative
animals
(Fig.
3). AL animals expressed 4 to 5 times more IL-12
p40 mRNA and PL animals expressed 7 to 20 times less
IL-12 p40
mRNA than normal animals. Despite apparent differences,
-actin
production may be changed by viral antigens. To confirm that
differences
in IL-12 p40 mRNA expression in PL animals was not
influenced
by a change in
-actin mRNA expression, total RNA was
isolated
and the amount of IL-12 p40 mRNA per microgram of total RNA
was
quantitated. Again, AL animals expressed approximately twice the
amount of IL-12 p40 mRNA than normal animals did, while PL animals
produced four times less IL-12 p40 mRNA per microgram of total
RNA than
normal animals did (Fig.
4). Thus, IL-12
p40 mRNA production
by AL animals increased and that by PL animals
decreased relative
to that by normal animals, when measurements of
either mRNA or
total RNA were used for comparison.
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FIG. 3.
Representative QC-PCR bands of -actin and IL-12 p40
produced by BLV-infected animals with different stages of disease and
by a normal (BLV) animal. (a) Isolated mRNA was amplified
by using a fixed amount of mimic DNA. (b) The concentration of IL-12
p40 mRNA (in attomoles per picomole of -actin) was calculated.
Standard error bars are shown.
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FIG. 4.
Concentrations of IL-12 p40 mRNA (in attomoles per
microgram of total RNA) expressed by BLV-infected animals with
different stages of disease and by normal (BLV) animals.
An equal amount, 0.5 µg, of total RNA was amplified by using a fixed
concentration of mimic IL-12 p40. Three to five animals were used for
each disease stage. Standard error bars are shown.
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|
IL-12 is produced only by monocytes/macrophages.
To determine
the cell type producing IL-12 p40, monocytes/macrophages were isolated
from PBMCs of AL animals by using mouse anti-bovine CD14 antibodies
(CAM36A; Veterinary Medical Research and Development, Inc., Pullman,
Wash.) and goat anti-mouse immunoglobulin G (IgG)-coated magnetic beads
(Dynal, Lake Success, N.Y.) and confirmed by esterase staining
(24). More than 90% of the CD14 positively selected
cells exhibited dark brown 
-naphthyl acetate staining, while the
negatively sorted cell population stained yellow. THP-1 (ATCC TIB202),
a human monocyte cell line, was used as a positive control and
Daudi (ATCC CCL 213), a human B-cell line, was used as the negative
control. By using RT-PCR, IL-12 p40 mRNA expression was detected only
in the positively sorted monocytes/macrophages, not in the negatively
selected cells (Fig. 5). We also
determined that IFN- mRNA was detected in negatively isolated cells
(Fig. 5), consisting predominantly of T and B lymphocytes as determined
by flow cytometry (data not shown). However, IFN- mRNA was not
expressed by positively sorted cells, while -actin was
constitutively expressed from both positively and negatively sorted
cells. Thus, increased IL-12 p40 mRNA expression in PBMCs of AL animals
is from monocytes/macrophages.
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FIG. 5.
IL-12 p40 mRNA expression by sorted
monocytes/macrophages. Monocytes/macrophages were separated by use of
magnetic beads. Mouse anti-bovine CD14 antibody was used, followed by
goat anti-mouse IgG-coated magnetic beads. Sorted monocytes/macrophages
were confirmed by esterase staining. -actin was used to confirm the
RT-PCR results and that a similar product was evident in different
animals and isolated cell populations. IFN- transcription was used
to confirm the separation of T cells from the monocyte/macrophage
population. M , macrophages.
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|
The results presented here demonstrate that IL-12 p40 mRNA was produced
at relatively high concentrations by freshly isolated
PBMCs of
BLV-infected animals in the AL disease stage and at significantly
reduced levels in PL animals. Biological activity of IL-12 is
derived
from the heterodimer p70, composed of p40 and p35, and
the homodimer
p40 could be an antagonist for IL-12 activity, binding
the IL-12
receptor in the murine system (
15). However, p35 IL-12
mRNA
is constitutively expressed by nonhemapoietic tissues as
well as
lymphoid cells, while p40 IL-12 mRNA expression is regulated
upon
immune stimulation and limited to lymphoid cells (
19,
37).
Therefore, even if IL-12 p40 is a nonfunctional subunit, the changes
in
IL-12 p40 mRNA expression may implicate the functional differences
in
BLV infection. Previously, we reported that IL-10 mRNA expression
increased with progression to the PL disease stage and that IL-2
and
IFN-
were reduced in PL and tumor-bearing animals (
29).
Together, our previous studies and present findings indicate that
the
type 1 immune response prevails in animals with the AL stage
of disease
and the cytokine profile converts to a type 2 response
in animals with
the more progressed PL stage of disease. Therefore,
the polarity of the
cytokine pattern is closely related to disease
progression in BLV
infection.
Whether the change in cytokine profile from type 1 to type 2 is a cause
or result of BLV disease progression is presently
unknown; however,
this cytokine profile shift may be initiated
by several mechanisms.
First, the change in cytokine polarity
may result directly from
cytokines produced by viral infection
or viral load. Type 1 cytokines
activate T cells, and activated
T cells may be eliminated by programmed
cell death; continuous
T-cell death may exhaust a type 1 immune
response (
10,
36).
Second, the amount of viral antigen may
lead to cytokine polarization.
Low antigen concentration can reportedly
trigger type 1 cytokine
production, while high amounts of antigen cause
a type 2 response
(
3,
31). In support of this mechanism, BLV
antigen is transcribed
in greater amounts in PL animals than in AL
animals (
16). Third,
particular regions of a peptide
sequence or the availability of
a viral protein may stimulate different
type of cytokines. For
example, HIV tat (
26) and gp120
(
2) proteins stimulate IL-10
production, while CKS-17, a
consensus transmembrane domain of
several retroviruses, inhibits type 1 cytokines and IL-12 production
(
17,
18). Similarly, BLV also
encodes tax and gp51 proteins,
which are homologous to HIV tat and
gp120, while BLV gp30 has
a motif similar to that of CKS-17
(
17).
Presently, no BLV antigen that preferentially stimulates type 2 cytokine production is known. However, evidence exists that
naturally
occurring variants of other viruses, including HIV,
can antagonize
cytotoxic T-cell responses (
5,
21). Selected
mutant viral
antigens can alter the binding affinity of peptides
to major
histocompatibility complex molecules or recognition by
T-cell receptors
(
9). Since BLV infection can persist for years
in an animal,
accumulation of proteins with altered peptides possessing
different
binding affinities to major histocompatibility complex
molecules or
T-cell receptors is possible. In fact, variants of
gp51 have been
reported (
27), reenforcing this possibility.
Infected
animals with minimal virus production and minimal antigenic
variation
would maintain high-affinity ligand interactions promoting
type 1 cytokines in the AL stage. In contrast, once sufficient
variants
with low-affinity peptides are generated, the T-cell
response would be
altered, with production of type 2 cytokines
with disease progression
to the PL stage.
We also found that IL-12 p40 mRNA was expressed by PBMCs from
tumor-bearing animals. IL-12 expression was detected in
AIDS-related
lymphoma B-cell lines, and the antagonistic effect of
IL-10 on
IL-12 does not apply to these B cells because they are tumor
cells
(
4). Thus, despite high expression of IL-10, IL-12 p40
was
also produced by BLV-infected tumor-bearing animals. However,
further research was not possible due to the death of the tumor-bearing
animals. Host immune response with differing cytokine expression
may
influence viral replication and virus control by the host.
For example,
T cells from AL animals have more efficient
cytotoxic-T-lymphocyte
activity than those from PL animals
(
25). High titers of virus
exist in the PL stage, supporting
the inability of PL animals
to effectively control BLV infection. IL-12
is an important cytokine
for promoting cytotoxic-T-lymphocyte activity
and regulating the
cell-mediated immune response. In contrast, an
increased level
of IL-10 in HIV infection suppressed HIV replication by
monocytes/macrophages
(
1,
6), while IL-12 enhanced HIV
replication in PBMCs (
13).
Therefore, decreased IL-12 and
increased IL-10 in PL animals may
further inhibit BLV replication. We
have observed that IL-10 significantly
inhibits BLV
tax and
pol expression (
28). Further studies to
examine
the in vitro effects of other cytokines such as IL-2 and
IL-12 on viral
replication would aid in understanding the mechanism
of cytokine
polarization in BLV infection. The cytokine patterns
in BLV infection
and IL-12 expression appear important in the
regulation of disease
progression.
| |
ACKNOWLEDGMENTS |
We thank Kathy L. O'Reilly for providing a blood sample from a PL
animal and Yeon-Soo Han for help with photography.
This work was supported by National Cancer Institute grant R01 CA59127,
BARD 95-34339-2556, and the College of Agricultural and Life Sciences.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Animal Health and Biomedical Sciences, University of
WisconsinMadison, 1655 Linden Dr., Madison, WI 53706. Phone: (608)
262-1837. Fax: (608) 262-7420. E-mail:
gas{at}ahabs.wisc.edu.
| |
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J Virol, August 1998, p. 6917-6921, Vol. 72, No. 8
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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