Department of Internal Medicine, Pulmonary and Critical Care Division, University of Oklahoma Health Sciences Center; and the Program in Molecular and Cellular Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
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ABSTRACT |
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The adenovirus
(Ad) early gene product 13S transactivates the tumor necrosis factor
(TNF)- promoter in inflammatory cells. We examined both the
subdomains of E1A and the upstream TNF promoter elements involved. In
both Jurkat and U-937 cells, zinc finger or carboxyl region mutation of
Ad E1A 13S conserved region 3 resulted in a significant loss of
transactivation of the TNF promoter (
69%). For both cell types there
was a TNF-negative regulatory element in the
242 to
199 region and
a positive regulatory element between
199 and
118. In contrast, an
upstream positive regulatory element was detected in different regions
in both cell types. In U-937 cells the positive regulatory unit was
between
600 and
576, whereas in Jurkat cells it was between
576
and
242. The U-937 upstream element was dependent on a site
previously designated epsilon in cooperation with an adjacent nuclear
factor-
B-2a site. Therefore, transactivation of the TNF promoter by
Ad 13S in lymphocyte and monocyte cell types involves similar
subdomains of the E1A protein, but cell-specific TNF promoter elements.
Adenoviridae; human gene expression/regulation; Jurkat cells; transactivation; U-937 cells; virus replication; zinc finger protein; third conserved region
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INTRODUCTION |
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ADENOVIRAL INFECTION CAUSES pneumonia and disseminated disease in immunocompromised and nonimmunocompromised hosts (1, 7, 33). Chronic sequelae of inflammation also occur, including bronchiectasis, bronchiolitis obliterans, and hyperlucent lung syndrome (12, 17, 30-32). In addition, persistence of adenovirus or its proteins has been suggested as a risk factor for the development of steroid-resistant childhood asthma and chronic obstructive lung disease in some patients (21, 22).
Expression of adenovirus early genes may be important in mediation of
inflammation by adenovirus, as infection in animal models with
nonreplicating virus results in inflammation that is quantitatively similar to active infection (10, 11, 25). Tumor necrosis factor (TNF)- is elevated in lung homogenates of these animals, suggesting that induction of this cytokine is important in the inflammatory response to adenovirus (11). TNF infusion
causes inflammation in many animals (2, 35, 37).
Furthermore, TNF appears to mediate many other forms of lung injury
triggered by a variety of inciting agents (1, 6, 18).
We previously demonstrated that one of the gene products of the adenovirus early gene region E1A 13S transactivates the TNF gene in inflammatory cells (23). In that study, the third conserved region (CR3) of 13S appeared to be responsible for this effect, as transactivation was not seen with the 12S protein lacking this region. There are two subdomains of this CR3, a zinc finger and carboxyl region domain. Both of these subdomains are important for transactivation of downstream promoter elements of adenovirus (40). The first objective of this current study was to determine whether these subdomains are also important for transactivation of the TNF promoter by adenovirus in inflammatory cells.
The TNF promoter contains consensus sequences for many transcription factor binding sites (8, 14, 27). The importance of individual sites varies depending on the stimulus and cell type used (13, 27). We also sought to determine which regions of the TNF promoter are important for transactivation of the TNF promoter by adenovirus.
Our findings demonstrate that 1) both subdomains of E1A CR3 are necessary for transactivation of the TNF promoter by adenovirus and 2) discrete and cell-type specific regions of the TNF promoter are important for these effects.
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MATERIALS AND METHODS |
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Cell culture.
Jurkat (ATCC TIB 152) and U-937 (ATCC CRL-1593.2) cell lines, obtained
from American Type Culture Collection (Rockville, MD), were used for
these studies, as adenoviruses infect both lymphocytes and
monocyte/macrophages (5, 19). The Jurkat line was
derived from a cell line established from a patient with T-cell
leukemia. This derived line produces interleukin (IL)-2 and
interferon- on stimulation and is CD2+,
CD3+, CD4
, and CD8
. The U-937
line was derived from a patient with acute histiocytic lymphoma, has Fc
and C3 receptors, produces lysozymes, and is phagocytic. Both cell
types were maintained in suspension cell culture in RPMI 1640 medium
containing 10% fetal bovine serum (Hyclone Laboratories, Logan, UT), 2 mM L-glutamine, and 80 µg/ml gentamicin.
Plasmids.
The plasmid (p) SKE1AWT codes for the wild-type (WT) E1A 13S
289R protein under control of the native adenovirus
promoter. pSKC171S and pSKS185N contain mutations
resulting in single amino acid substitutions in the carboxyl (S185N)
and zinc finger (C171S) subdomains of the CR3. pSKC171S/S185N encodes a
double mutant of CR3. pSKT178S contains a mutation causing a single
amino acid substitution in the region between the zinc finger and
carboxyl region subdomains. All of these plasmids were gifts of Dr.
Robert Ricciardi (Wistar Institute, Philadelphia, PA)
(40). The parent control plasmid Bluescript II
SK (pBIISK
) was obtained from
Stratagene (La Jolla, CA). The TNF promoter-CAT reporter
constructs contain serial 5' deletions of the human TNF promoter
(
600,
576,
242,
118,
80,
52) upstream of the protein coding
region of bacterial chloramphenicol acetyltransferase and were kindly
given by Dr. A. Goldfeld (14). The human
immunodeficiency virus (HIV)-1 long terminal repeat (LTR) promoter-CAT
construct pHIV-1, which contains the HIV-1 LTR
450 to +180 upstream
of CAT, was kindly given by Dr. B. M. Peterlin (34).
This construct was used to determine whether transactivation by
adenovirus E1A was specific in the cells tested. HIV-1 LTR is not
transactivated by E1A 13S in Jurkat, THP-1, or HeLa cells (28,
38). The thymidine kinase-
-galactosidase plasmid
(pTK-
-gal) contains the herpes simplex virus thymidine kinase
promoter linked to the
-gal protein-coding gene and was constructed
from the pSV-
-gal (Promega) and pMC1neo poly-A
(Stratagene). It was used to confirm similar transfection efficiencies between separate experiments (40). The
plasmids used to determine whether TNF protein production is enhanced
by E1A were pE1A-WT, p13S-WT, and p12S-WT, which were kindly given by
Dr. Elizabeth Moran (24). These plasmids express either
all the native proteins from the E1A region, WT E1A 13S 289R, or WT E1A
12S 243R, respectively. The parent vector for these constructs pUC18
was used as a negative control (GIBCO-BRL, Rockville, MD).
Transient transfections.
Transfection of both cell types was performed by electroporation. Cells
were resuspended at a concentration of 2.5 × 107
cells/ml (Jurkat cells) or 1.0 × 107 cell/ml (U-937
cells) in the same medium used for culture (see Cell
culture). Plasmid DNA was added to 0.4 ml of this cell
suspension in 0.4-cm electroporation cuvettes; the cells were gently
mixed and were then electroporated at settings of 950 µF and 0.29 V. The electroporated cells were then transferred to 10-cm culture dishes
with 10 ml of culture medium. Viability of the cells after electroporation was 35-53% as determined by trypan blue
exclusion. For each transfection, additional cells were transfected in
triplicate with 10 µg of pTK- for later
-gal assays. After
48 h of culture, cells were collected for CAT and
-gal assays.
E1A protein expression by transfected cells was confirmed by Western
analysis as previously described (23).
CAT assays.
CAT assays were performed as described using butyrylated coenzyme A
(Sigma, St. Louis, MO) (29). Cell extract protein was measured by the method of Bradford (4), and equal amounts
of protein were used for assays. The 14C-labeled
chloramphenicol (NEN/Perkin Elmer, Boston, MA) was separated into
unbutyrylated and butyrylated derivatives by phase extraction using
mixed xylene (Sigma), and the butyrylated derivatives were quantified
by liquid scintillation. CAT activity was interpolated from a standard
curve derived from dilutions of purified chloramphenicol acetyltransferase. The assay was linear over about three orders of
magnitude of CAT, and all assays were performed in the linear range of
the assay. The results were adjusted for -gal activity from cells
transfected separately with pTK-
to control for variations in
transfection efficiency.
TNF- protein determination.
U-937 cells were transfected with 40 µg of pE1A-WT, p13S-WT, p12S-WT,
or pUC18 as described. After 48 h of incubation, 106
viable cells/ml were transferred to 12-well plates in fresh medium and
stimulated with 1, 10, or 100 ng/ml phorbol 12-myristate 13-acetate (PMA; Sigma) or were mock stimulated with dimethyl sulfoxide (DMSO). After incubation for an additional 24 h, the media supernatants were collected and analyzed in triplicate for TNF-
protein by a
sandwich enzyme-linked immunosorbent assay that has a sensitivity of
15 pg TNF-
/ml (R&D Systems, Minneapolis, MN). The interassay variability of a TNF-
control standard was ± 3.8% SD.
-Gal assays.
-Gal assays were performed by a chemiluminescent assay
(Tropix, Bedford, MA). The assay is sensitive to 2 fg of
-gal and linear over approximately five orders of magnitude.
Statistical analysis. The data are expressed as the means ± SE. Statistical significance was determined by either ANOVA with Ryan-Einot-Gabriel-Welsch multiple-range post hoc analysis or two-tailed t-test with Bonferroni correction for multiple comparisons as appropriate. Significance was considered as P < 0.05 (41).
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RESULTS |
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Effect of CR3 mutation of adenovirus E1A 13S on transactivation of
the TNF promoter in Jurkat and U-937 cells.
To evaluate the effect of mutation of specific regions of the
adenovirus E1A 13S CR3 on transactivation of the TNF promoter, we
cotransfected Jurkat cells and U-937 cells with E1A CR3 mutant plasmids
(Fig.1A)
and the 600TNF promoter-CAT construct plasmid.
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Effect of 5'-TNF promoter deletion on transactivation by WT E1A 13S
in Jurkat and U-937 cells.
Mutation of specific subdomains of adenovirus E1A 13S had similar
effects on transactivation of the TNF promoter in both Jurkat and U-937
cell lines. Therefore, we subsequently used 5'-TNF promoter deletions
to determine whether similar regions of the TNF promoter were activated
by E1A in both cell types (Fig.
2A). By
comparing the relative activities of adjacent promoter deletions, we
could infer the presence of either positive or negative regulatory
elements.
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Cell-specific activation of the distal TNF promoter region.
The 24-bp region between 600 and
576 contains two transcription
factor binding sites. NF-
B-2a has been shown to bind NF-
B proteins, as has a second site know as
, both in response to lipopolysaccharide (LPS) stimulation. The
-site also binds a non-NF-
B protein constitutively (36). We first sought
to confirm the cell-specific activity of the 24-bp segment in response
to E1A transactivation and to determine whether this activity was due
to the NF-
B-2a site. We performed transient transfections in Jurkat
and U-937 cells with the pSKE1AWT expression vector or the control
plasmid along with the proximal deletion
52 or the
52 proximal
deletion to which an NF-
B-2a triplet or the 24-bp region had been
added. Data are expressed as CAT activity relative to that seen with
cells transfected with pSKE1AWT and the
600TNF promoter construct.
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Effect of CR3 mutation of adenovirus E1A 13S on transactivation of
the 600- to
576TNF promoter.
To determine whether transactivation of the 24-bp region occurred
through similar subdomains of adenovirus E1A 13S CR3 as for
transactivation of the entire promoter, U-937 cells were cotransfected with the 24-bp TNF construct and either the WT or CR3 mutant adenovirus E1A 13S expression vectors (Fig. 4).
These results mirror those obtained with the intact
600TNFCAT
(Fig. 1C). CAT activity is expressed as a percentage of that
seen in cells transfected with pSKE1AWT and p24bpTNFCAT.
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Localization of the TNF promoter upstream positive regulatory
element in U-937 cells.
To determine the active site for transactivation in the 600- to
576TNF promoter region, we introduced mutations in the
-site, the
NF-
B-2a site, or both, and cotransfected the constructs along with
the WT E1A 13S expression vector or control plasmid. CAT activity was
expressed as a percentage of the 24-bp TNF construct, which contains no
mutations (Fig. 5A).
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TNF protein induction by adenovirus E1A. To determine whether induction of the TNF promoter by E1A under control of the native adenovirus promoter resulted in induction of TNF protein production, we transfected U-937 cells with plasmids expressing all proteins from the E1A region (pE1A-WT), the 13S protein (p13S-WT), or the 12S protein (p12S-WT). Transfection with the control vector pUC18 was used as a negative control. Cells were also stimulated with increasing concentration of PMA or were left unstimulated.
E1A 13S expression by unstimulated U-937 cells resulted in at least a 2.2-fold increase in TNF protein production over unstimulated control cells (33 ± 8 vs. <15 pg/ml; Fig. 6). TNF protein production from U-937 cells expressing E1A 13S and stimulated with 10 ng/ml PMA displayed a significant 2.3-fold increase compared with identically treated control cells (456 ± 30 vs. 198 ± 21 pg/ml, P < 0.05). Similarly, at 100 ng/ml PMA, a significant 2.8-fold increase in TNF protein was induced by cells expressing E1A 13S compared with identically stimulated control cells (598 ± 43 vs. 210 ± 23 pg/ml, P < 0.05). Additional experiments confirmed this effect is specific for E1A 13S, as transfection with plasmids expressing all the E1A proteins (WT E1A) or the E1A 12S (WT E1A 12S) protein did not enhance TNF protein production, even in the presence of PMA (Fig. 6). These results confirm that the presence of E1A 13S in mitogen-stimulated, monocyte/macrophage-like cells significantly enhances TNF protein production.
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DISCUSSION |
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Stimulation of TNF- by adenovirus early proteins expressed
during replicative infection or latency may well play a role in chronic
inflammation due to adenovirus. The current results confirm and extend
previous data demonstrating upregulation of the TNF gene by adenovirus
E1A 13S in inflammatory cells. (23) The importance of the
specific subdomains in the CR3 necessary for transactivation of the TNF
promoter by adenovirus is demonstrated. Localizing the sites within the
E1A 13S CR3 responsible for transactivation suggests which of several
mechanisms are responsible for the findings demonstrated.
There are three conserved regions in the adenovirus 13S 289R protein: CR1, CR2, and CR3 (20). Only CR1 and CR2 are also present in the shorter 12S 246R protein. We previously demonstrated that transactivation of the TNF promoter occurs only with the CR3-containing 13S protein and not with the 12S protein, which contains only CR1 and CR2 (23). In the present study, we confirm the importance of the E1A 13S CR3 in TNF promoter transactivation by demonstrating loss of this activity with deletion in either or both of two putative subdomains of the CR3.
Transcriptional activation by adenovirus E1A 13S CR3 appears to occur indirectly by binding of the subdomains to general and specific transcription factors. The zinc finger subdomain [amino acid (aa) 147-177] interacts with the general transcription factor IID through binding to TATA-binding protein (TBP) and TBP-associated factors, whereas the carboxyl region (aa 180-188) binds to cellular or specific transcription factors (9). E1A thus acts as a type of coactivator by linking cell specific transcription factors and the basal transcriptional complex. In this way E1A alters transcription rates without binding to DNA specifically in vitro.
As the target of E1A-mediated transactivation, the TNF promoter
includes consensus sequences for many transcription factors, including
activator protein (AP)-1, AP-2, and cAMP response elements (CRE)
(16, 26, 27). Also, there are multiple sites for NF-B (13). It appears that the importance of these sites varies
with the cell type and stimulus used. Rhoades and colleagues
(26), evaluating promoter transactivation by E1A in U-937
cells and a gibbon T-lymphocyte line, concluded that CRE were important for this activity in T lymphocytes, whereas AP-1 and AP-2 sites were
also important in U-937 cells according to mutational analysis of these
sites. The authors ascribed no importance to TNF promoter sequences
upstream of
120 or to NF-
B sites in either cell type, despite the
demonstration of a strong regulatory element between
615 and
120.
They also did not perform any mutations of putative NF-
B sites, and
although they used AP-1, AP-2, and CRE expression vectors to confirm
their findings, they did not use any method to increase NF-
B
expression and evaluate this effect on E1A transactivation. With regard
to this region, Udalova and colleagues (36), using a
variety of different methods and mutational analysis in the
600TNF
promoter region, implicated multiple NF-
B sites, including an
NF-
B-like site and a site termed
as important in stimulation of
the TNF promoter by LPS in Mono Mac 6 cells. Our findings confirm that
these sites, particularly
and NF-
B-2a, are important for transactivation of the TNF promoter by E1A in the
monocyte/macrophage-like U-937 cells.
It is important that the sites in this region in E1A transactivation of
TNF is cell type dependent. Comparing data from the Jurkat and U-937
cells, it appears that the NF-B-2a and
containing
600 to
576
region is not active in Jurkat cells.
Previous studies in our laboratory using E1A in a dextran-transfected
monocyte/macrophage THP-1 cell line showed minimal induction of TNF
mRNA but did not demonstrate induction of TNF protein
(23). In the study by Rhoades et al. (26),
E1A controlled by the stronger Rous sarcoma virus promoter was shown to
induce IL-8 protein. In the data presented here, we
demonstrate that E1A controlled by its native adenovirus promoter
enhances TNF protein production from electroporated U-937 cells, at
least in the presence of PMA. This effect was not due to enhancement of
E1A expression by PMA, as Western analysis for E1A from PMA-stimulated
E1A-transfected U-937 cells did not show enhanced E1A protein
expression (not shown). Enhancement of TNF production by PMA in
E1A-transfected cells is likely related to NF-B activation, perhaps
in association with AP-1, because modest induction of NF-
B binding
occurs in the presence of E1A, and PMA enhances NF-
B and AP-1
binding activity in monocyte/macrophage cells (3, 15). Our
findings using the various E1A region constructs in TNF protein
production experiments may provide insight into the mechanisms of
inflammation due to adenovirus infection and subsequent expression of
the native E1A proteins. The WT E1A construct expresses all transcripts
from the E1A region, whereas the WT 12S construct expresses 12S but not
13S E1A. We did not find TNF induction with either of these constructs,
whereas expression of 13S E1A enhanced TNF protein production. This is
not surprising, as, with expression of 12S or the other E1A proteins,
CR1 and CR2, which have variable effects on DNA expression, would have
more influence on the overall results. These findings may relate to how
E1A expression stimulates inflammation in animal models. E1A gene
expression has been shown to enhance lung inflammation in vivo in
animal models in the presence of a cofactor such as cigarette smoke
(39). Our data suggest that this inflammation is likely
accompanied by or associated with specifically enhanced E1A 13S
expression, as expression of other E1A transcripts failed to induce
cytokine promoter activation in our model. We recognize that this would
have to be confirmed by measurements of specific transcripts or use of
E1A 13S protein-specific expression vectors in these animal models,
which has not been done.
In conclusion, we demonstrate a mechanism whereby an adenovirus protein can interact with specific promoter elements of the cytokine gene promoter. It appears that this occurs by interaction of specific conserved subdomains of the adenovirus E1A 13S protein with varying factors that bind to discrete but diverse regions of the TNF promoter that vary according to cell type.
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ACKNOWLEDGEMENTS |
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We thank Andrea Vincent for assistance with the statistical analysis and Drs. Gary Kinasewitz and Mark Coggeshall for review of the manuscript.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant K08-HL-03106 and an American Lung Association Research grant.
Address for reprint requests and other correspondence: J. P. Metcalf, Oklahoma Univ. Health Sciences Center, Research Park, Bldg. #1, 800 N. Research Pkwy, Rm. 425, Oklahoma City, OK 73104 (E-mail: jordan-metcalf{at}ouhsc.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.
April 26, 2002;10.1152/ajplung.00342.2001
Received 27 August 2001; accepted in final form 11 April 2002.
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