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CUTTING EDGE |
Department of Internal Medicine, Pulmonary and Critical Care Section, Yale University School of Medicine, New Haven, CT 06520
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and are important for protective
cell-mediated immune responses against intracellular microbes, but they
can also cause tissue injury in autoimmune diseases (3, 6). Th2 cells,
on the other hand, secrete IL-4 and IL-5 and protect against parasitic
infections but promote asthma and other allergic diseases (7). While
IL-4 stimulates IgE production, IL-5 promotes eosinophilic
inflammation in the airways of asthmatics. It appears that the differentiation of naive CD4+ T cells along the Th1 or Th2 pathway triggers different molecular events resulting in the differential expression of particular transcription factors in the two cell types. For example, we have previously shown that the transcription factor GATA-3 is expressed in Th2 but not Th1 cells and is critical for IL-5 gene expression (8). In a different study, GATA-3 was shown to be important and sufficient for the expression of other Th2 cytokine genes including IL-4, IL-6, and IL-10 (9). In these studies, ectopic expression of GATA-3 in the B cell line M12 was shown to be sufficient for activation of a minimal IL-4 promoter in the presence of phorbol ester and ionomycin (9). However, the GATA site(s) in the IL-4 promoter that conferred GATA-3-responsiveness was not characterized in this study (9). In the same study, the authors also showed that expression of antisense GATA-3 in Th2 cells affected IL-4 gene expression more than IL-5 gene expression (9). To sort out the apparently differential dependence on GATA-3 for IL-5 vs IL-4 gene expression, we attempted to define the GATA site(s) in the minimal IL-4 promoter that responded to GATA-3 in the studies reported by Zheng and Flavell (9). Our studies show that ectopic expression of GATA-3 alone can support IL-5 but not IL-4 gene induction in non-Th2 cells such as B cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rested D10 cells were transfected by electroporation as
described previously (8). After electroporation, the cells were left on
ice for 10 to 30 min, diluted to 5 ml with fresh medium, and incubated
at 37°C with or without anti-CD3 (at 10 µg/ml in wells coated
with the Ab), Ag + APC (8), dibutyryl cAMP
(bt2cAMP3; 1 mM)
+ PMA (25 ng/ml) (for IL-5 promoter-reporter constructs), or ionomycin
(1 µm) + PMA (100 ng/ml) (for the IL-4 promoter-reporter constructs).
Cells were harvested for reporter gene assays as described previously
(8). For M12 cell transfections, cells were grown in RPMI 1640, and at
10 h before transfection, the cells were transferred to fresh
medium. Electroporation conditions were the same as for D10 cells.
After electroporation, the cells were left in fresh medium for 2
h. The cells were left with or without the appropriate stimuli for
15 h and harvested for reporter gene assay. The Rous sarcoma
virus (RSV)-ß-galactosidase plasmid could not be used to
monitor transfection efficiency in M12 cells, since phorbol ester
stimulates multiple promoter/enhancers including RSV and CMV promoters
in M12 cells. For assessing cytokine production, 5 x
106 cells were electroporated with a total of 15 µg of
DNA containing 10 µg of expression vector containing GATA-3 cDNA in
either the sense (S) or antisense (AS) orientation. Cells were left
overnight at 37°C, and dead cells were removed by Ficoll density
gradient centrifugation. An equal number of live cells from each group
was split equally (8 x 105 cells per condition) and
either left untreated or treated with PMA+ bt2cAMP or with
PMA + ionomycin for 30 h. Supernatants were collected for ELISAs
(Endogen, Cambridge, MA); the lower limit of detection for both
cytokines was 5 pg/ml. Nuclear extracts prepared from cell pellets were
used in EMSAs.
Electrophoretic mobility shift assays
EMSAs were conducted as described previously using a double-stranded oligonucleotide containing the wild-type double GATA site present in the IL-5 promoter (8, 11). The sequence of the sense strand was -73CCTCTATCTGATTGTTAGCA-54; complementary oligonucleotides were annealed before use in EMSAs. The TNT wheat germ lysate system (Promega, Madison, WI) was used to obtain in vitro-translated GATA-3 protein. The Ab to GATA-3 was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-GATA-4 Ab was kindly provided by Dr. David Wilson (Washington University School of Medicine, St. Louis, MO).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our previous studies, we showed that a 1700-bp IL-5 promoter containing a mutation in a double GATA-3-binding site (located between -70 and -60 in the promoter) is completely unresponsive to either antigenic stimulation or stimulation with PMA + bt2cAMP in the prototypic murine Th2 clone, D10 (8). In a separate study, Zheng and Flavell showed that expression of antisense GATA-3 RNA in D10 cells only partially inhibits IL-5 gene expression but has a more pronounced effect on IL-4 gene expression (9). One possible explanation for the apparent discrepancy between our data and those of the other investigators is that GATA-3 binds with different affinities to target GATA sites in the IL-5 and IL-4 promoters. To test this hypothesis, we attempted to define the GATA site(s) in the IL-4 promoter that was responsible for GATA-3-dependent activation of the promoter in the studies reported by Zheng and Flavell (9).
For a head-to-head comparison between the effects of antisense GATA-3
RNA expression on IL-4 and IL-5 promoter activation, D10 cells were
transiently transfected with an IL-5 promoter-reporter plasmid or an
IL-4 promoter-reporter plasmid together with a mammalian expression
vector containing the full length cDNA for GATA-3, cloned in
the antisense (AS) orientation under the control of the RSV
promoter/enhancer. As shown in Figure 1
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expression of antisense GATA-3 RNA inhibited
anti-CD3-induced IL-5 promoter activity by 40% but had no
effect on IL-4 promoter activity. The control expression vector
transcribing the coding strand (S) of GATA-3 did not have
this effect. The likely explanation for incomplete inhibition of IL-5
promoter activation by this approach is the high basal expression of
GATA-3 mRNA (and protein) in D10 cells. Therefore, if the
IL-5 GATA site has a high affinity for GATA-3, residual GATA-3 activity
in the cells expressing antisense GATA-3 RNA may be
sufficient to support partial, if not full, activation of the IL-5
promoter. In fact, in the studies reported by Zheng and Flavell,
cells stably expressing antisense GATA-3 RNA had significant
residual GATA-3 protein levels and could efficiently support IL-5 but
not IL-4 gene expression (9).
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Since the antisense GATA-3 RNA expression studies failed to
provide any evidence for a GATA 3-responsive DNA sequence in the
800-bp IL-4 promoter, we used a more direct approach to test the
ability of GATA-3 to activate the IL-4 promoter. GATA-3 was ectopically
expressed in the murine B cell lymphoma line M12, and the cells were
cotransfected with either an IL-4 or an IL-5 promoter-reporter
construct. When the IL-5 promoter was
tested in this system, a small 2- to 4-fold activation was typically
observed with PMA + bt2cAMP alone in the absence of GATA-3
expression (Fig. 2A). In the presence of GATA-3 and PMA +
bt2cAMP, an increase in IL-5 promoter activity was observed
in a dose-dependent fashion with a net 30- to 40-fold activation with
the highest dose of GATA-3 expression vector (Fig. 2A). This finding was in keeping with our earlier studies in
other non-IL-5-producing cell lines, such as HeLa and the Th1 clone
A.E7, in which GATA-3 expression permitted activation of the IL-5
promoter (8). However, when the 800-bp IL-4 promoter was transfected
with the GATA-3 expression vector and the cells were
stimulated with PMA + ionomycin, no activation of the promoter was
observed (Fig. 2B). A shorter IL-4 promoter (-157 to +68)
that was reported to be responsive to GATA-3 in these cells (9) was
also unreponsive in our assays (Fig. 2B). The shorter
promoter had a much higher basal activity in the cells. Use of lower
amounts of the reporter construct led to activation of the promoter by
PMA + ionomycin alone (data not shown), which was not reflective of the
response of the endogenous gene in the B cells. Even at 20 µg of the
expression vector, we detected only a 2-fold increase in the basal
activity of the 157-bp promoter and no further increase upon
stimulation of the cells (data not shown).
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3A, M12 cells stimulated with
PMA + bt2cAMP and expressing GATA-3 sense but
not antisense RNA displayed an impressive induction of IL-5 production.
In contrast, while there was a small increase in the basal level of
IL-4 production by cells expressing the sense GATA-3 RNA,
the net production of IL-4 by the M12 cells was very little whether the
cells expressed GATA-3 sense or antisense RNA, even upon
stimulation with PMA + ionomycin. The expression of GATA-3 in the M12
cells was comparable to expression in D10 cells as judged by EMSA (Fig. 3B). Thus, it appears that GATA-3 expression in a non-Th2
environment is insufficient for IL-4 gene expression but is sufficient
for IL-5 gene expression.
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We previously described the presence of a double GATA site in the IL-5 promoter, located between -70 and -60, which bound GATA-3, and was critical for activation of the promoter by multiple stimuli (8, 11). In a more recent study, Lee et al. also demonstrated a crucial role for this GATA site in IL-5 promoter activation in Th2 cells (10). Here, we show that both of the GATA elements are important for IL-5 promoter activity in Th2 cells. Similar to a mutation affecting both the GATA elements (mut 3), mutation of either element (mut 1 or mut 2) in the context of the 1700-bp promoter abolished promoter activity (Fig. 4A). As we reported previously (8, 11), while a promoter containing a mutation in the activator protein 1 (AP-1)-like site within the CLE0 element located between -53 and -39 was totally inactive, one containing a mutation in an NF-AT element was fully active in these assays.
In our previous studies we showed that the double GATA site forms two
complexes (I and II) with nuclear proteins isolated from either D10
cells or from in vitro-differentiated murine CD4+ T cells
(8). To further characterize the two DNA-protein complexes, we allowed
in vitro-translated GATA-3 to interact with the IL-5 GATA doublet and
analyzed the binding reaction in EMSAs along with binding reactions set
up with nuclear extracts prepared from anti-CD3-stimulated D10
cells. As shown in Figure 4B, complex I comigrated with the
complex formed with the in vitro-translated protein and most likely
represents interactions with the GATA-3 homodimer. Complex II probably
contains heterodimeric GATA-3. In accordance with the functional data
presented in Figure 4A, the formation of complexes I and II
required both GATA elements. The identity of the proteins present in
the complex formed with the mut. 2 probe is unknown and probably
represents nonspecific binding. This complex did not contain GATA-3
since its formation could not be supershifted/inhibited by the
anti-GATA-3 Ab. Taken together, the functional studies and the
DNA-binding experiments suggest that both GATA elements within the
doublet contribute to activation of the IL-5 promoter by GATA 3.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50-fold) by GATA-3 expression alone in PMA + ionomycin-stimulated
M12 cells (9), our studies failed to detect any activation of either an
800 bp IL-4 promoter fragment or the shorter -157/+68 fragment in
M12 cells in the presence of GATA-3 and a combination of PMA and
ionomycin. However, in keeping with our earlier observations with two
other non-IL-5-producing cell types HeLa and A.E7 (Th1) cells (8),
ectopically expressed GATA-3 in M12 cells efficiently supported IL-5
promoter activation in a dose-dependent fashion. IL-5 promoter activation needs at least two DNA elements–the double GATA site and an AP-1-like site within a CLE0 element as previously described by us (8, 11). Since GATA-3 expression alone is sufficient to activate the IL-5 promoter in different cell types when the cells are also stimulated with PMA + bt2cAMP, stimulation of the cells most likely triggers the binding of similar proteins to the AP-1-like site in all cell types. Using nuclear proteins derived from either in vitro-differentiated murine Th1 and Th2 cells or from T cell clones, we have shown that the DNA-protein complex formed with the AP-1-like site with either cell extract contains JunB and JunD (8, 11). Therefore, neither JunB nor JunD appears to be expressed in a Th2-specific fashion. In fact, both JunB and JunD have been implicated in IL-2 gene transcription in Th1 cells (12).
The individual GATA elements in the double GATA site in the IL-5
promoter are present in an inverse orientation with respect to each
other and are located between -70 and -65 and between -65 and -60.
The first sequence conforms with the WGATAR consensus sequence. The
second site has an intact GAT core but has a T instead of A in the +1
position. However, it appears that this substitution can still be
selected by GATA-3, particularly within overlapping GATA sites (13).
Overlapping GATA sites have also been previously identified in many
erythroid-expressed genes such as the chicken 
-globin promoter (14).
Overlapping and/or multiple GATA sites appear to confer increased GATA
binding activity and may play a key role in differential responsiveness
to GATA-3 for different genes (14, 15, 16). It is important to note, in
this context, that the region between -157 and +68 in the IL-4
promoter does not have any double GATA sites and that the single GATA
sites located in this region are not sensitive to GATA-3 activation.
Also, although there is a double GATA site located between -264 and
-274 in the IL-4 promoter (17), this site is unresponsive to
transactivation by GATA-3. These two GATA sites
(-274TGATAAGATTA-264) are present as direct
repeats, unlike the inverted repeats found in the IL-5 promoter (Fig. 3). In the studies of Ko and Engel, in which binding of GATA-3 to
random oligonucleotides was assessed, GATA-3 was found to select
oligonucleotides containing inverted GATA repeats much more frequently
than those containing GATA sites as direct repeats (13). Thus, our
studies lend functional credence to the studies of Ko and Engel (13)
and suggest that sensitivity to GATA-3 is dictated by inverted double
GATA sites.
While a direct involvement of GATA-3 in IL-5 promoter activation has been demonstrated in our studies (8) as well as in those of Lee et al. (10), a similar direct role for GATA-3 in IL-4 promoter activation is not evident in our studies. Therefore, the logical question that arises is how GATA-3 activates IL-4 gene expression in Th2 cells. Based on the recent reports from various laboratories, it seems likely that IL-4 gene expression needs multiple factors such as c-Maf (18), NF-ATc (19, 20), or NF-IL6 (21, 22), which probably act in concert with GATA-3 to induce gene expression. Interestingly, it was recently shown that although NF-ATc-/-/RAG-1-/- mice contained a full complement of GATA-3 activity, the mice were deficient in IL-4 gene expression, indicating that the presence of GATA-3 is not sufficient to support IL-4 gene expression (20). It appears that the GATA site that confers responsiveness to GATA-3 in the IL-4 gene is located elsewhere in the IL-4 gene and has yet to be identified. Indeed, studies of Wenner et al. indicate that the 800-bp IL-4 promoter lacks sufficient information for maximal expression of the IL-4 gene (23). Thus, collectively it appears that although the IL-4 and IL-5 genes are most often coordinately expressed in Th2-type cells, GATA-3 is sufficient for optimal expression of the IL-5 but not the IL-4 gene.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Anuradha Ray, Department of Internal Medicine, Pulmonary and Critical Care Section, Yale University School of Medicine, 333 Cedar Street, LCI 105, New Haven, CT 06520. E-mail address:
3 Abbreviations used in this paper: bt2cAMP, dibutyryl cAMP; RSV, Rous sarcoma virus; EMSA, electrophoretic mobility shift assay; AP-1, activator protein 1.
Received for publication June 10, 1998. Accepted for publication August 12, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C. Lavenu-Bombled, C. D. Trainor, I. Makeh, P.-H. Romeo, and I. Max-Audit Interleukin-13 Gene Expression Is Regulated by GATA-3 in T Cells. ROLE OF A CRITICAL ASSOCIATION OF A GATA AND TWO GATG MOTIFS J. Biol. Chem., May 17, 2002; 277(21): 18313 - 18321. [Abstract] [Full Text] [PDF]
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C. B. Stephensen, R. Rasooly, X. Jiang, M. A. Ceddia, C. T. Weaver, R. A. S. Chandraratna, and R. P. Bucy Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway J. Immunol., May 1, 2002; 168(9): 4495 - 4503. [Abstract] [Full Text] [PDF]
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H. Kurata, H.-J. Lee, T. McClanahan, R. L. Coffman, A. O'Garra, and N. Arai Friend of GATA Is Expressed in Naive Th Cells and Functions As a Repressor of GATA-3-Mediated Th2 Cell Development J. Immunol., May 1, 2002; 168(9): 4538 - 4545. [Abstract] [Full Text] [PDF]
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L. J. Kieffer, J. M. Greally, I. Landres, S. Nag, Y. Nakajima, T. Kohwi-Shigematsu, and P. B. Kavathas Identification of a Candidate Regulatory Region in the Human CD8 Gene Complex by Colocalization of DNase I Hypersensitive Sites and Matrix Attachment Regions Which Bind SATB1 and GATA-3 J. Immunol., April 15, 2002; 168(8): 3915 - 3922. [Abstract] [Full Text] [PDF]
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 J. P. Justice, M. T. Borchers, J. J. Lee, W. H. Rowan, Y. Shibata, and M. R. Van Scott Ragweed-induced expression of GATA-3, IL-4, and IL-5 by eosinophils in the lungs of allergic C57BL/6J mice Am J Physiol Lung Cell Mol Physiol, February 1, 2002; 282(2): L302 - L309. [Abstract] [Full Text] [PDF]
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 A. L. Wurster, D. J. Withers, T. Uchida, M. F. White, and M. J. Grusby Stat6 and IRS-2 Cooperate in Interleukin 4 (IL-4)-Induced Proliferation and Differentiation but Are Dispensable for IL-4-Dependent Rescue from Apoptosis Mol. Cell. Biol., January 1, 2002; 22(1): 117 - 126. [Abstract] [Full Text] [PDF]
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M. Zhou, W. Ouyang, Q. Gong, S. G. Katz, J. M. White, S. H. Orkin, and K. M. Murphy Friend of GATA-1 Represses GATA-3-dependent Activity in CD4+ T Cells J. Exp. Med., November 12, 2001; 194(10): 1461 - 1471. [Abstract] [Full Text] [PDF]
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A. Boonstra, F. J. Barrat, C. Crain, V. L. Heath, H. F. J. Savelkoul, and A. O'Garra 1{alpha},25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells J. Immunol., November 1, 2001; 167(9): 4974 - 4980. [Abstract] [Full Text] [PDF]
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H. Kishikawa, J. Sun, A. Choi, S.-C. Miaw, and I-C. Ho The Cell Type-Specific Expression of the Murine IL-13 Gene Is Regulated by GATA-3 J. Immunol., October 15, 2001; 167(8): 4414 - 4420. [Abstract] [Full Text] [PDF]
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A. Wensky, M. C. Garibaldi Marcondes, and J. J. Lafaille The Role of IFN-{gamma} in the Production of Th2 Subpopulations: Implications for Variable Th2-Mediated Pathologies in Autoimmunity J. Immunol., September 15, 2001; 167(6): 3074 - 3081. [Abstract] [Full Text] [PDF]
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M. C. Nawijn, G. M. Dingjan, R. Ferreira, B. N. Lambrecht, A. Karis, F. Grosveld, H. Savelkoul, and R. W. Hendriks Enforced Expression of GATA-3 in Transgenic Mice Inhibits Th1 Differentiation and Induces the Formation of a T1/ST2-Expressing Th2-Committed T Cell Compartment In Vivo J. Immunol., July 15, 2001; 167(2): 724 - 732. [Abstract] [Full Text] [PDF]
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J. Kim, K. Uyemura, M. K. Van Dyke, A. J. Legaspi, T. H. Rea, K. Shuai, and R. L. Modlin A Role for IL-12 Receptor Expression and Signal Transduction in Host Defense in Leprosy J. Immunol., July 15, 2001; 167(2): 779 - 786. [Abstract] [Full Text] [PDF]
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J.C. Kips, K.G. Tournoy, and R.A. Pauwels New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5 Eur. Respir. J., March 1, 2001; 17(3): 499 - 506. [Abstract] [Full Text] [PDF]
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 J. C. Keen, L. Sholl, M. Wills-Karp, and S. N. Georas Preferential Activation of Nuclear Factor of Activated T Cells c Correlates with Mouse Strain Susceptibility to Allergic Responses and Interleukin-4 Gene Expression Am. J. Respir. Cell Mol. Biol., January 1, 2001; 24(1): 58 - 65. [Abstract] [Full Text]
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N. Takemoto, Y. Kamogawa, H. Jun Lee, H. Kurata, K.-i. Arai, A. O'Garra, N. Arai, and S. Miyatake Cutting Edge: Chromatin Remodeling at the IL-4/IL-13 Intergenic Regulatory Region for Th2-Specific Cytokine Gene Cluster J. Immunol., December 15, 2000; 165(12): 6687 - 6691. [Abstract] [Full Text] [PDF]
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C.-H. Chen, D.-H. Zhang, J. M. LaPorte, and A. Ray Cyclic AMP Activates p38 Mitogen-Activated Protein Kinase in Th2 Cells: Phosphorylation of GATA-3 and Stimulation of Th2 Cytokine Gene Expression J. Immunol., November 15, 2000; 165(10): 5597 - 5605. [Abstract] [Full Text] [PDF]
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 L. H. Glimcher and K. M. Murphy Lineage commitment in the immune system: the T helper lymphocyte grows up Genes & Dev., July 15, 2000; 14(14): 1693 - 1711. [Full Text]
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H. J. Lee, N. Takemoto, H. Kurata, Y. Kamogawa, S. Miyatake, A. O'Garra, and N. Arai Gata-3 Induces T Helper Cell Type 2 (Th2) Cytokine Expression and Chromatin Remodeling in Committed Th1 Cells J. Exp. Med., July 3, 2000; 192(1): 105 - 116. [Abstract] [Full Text] [PDF]
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A. Y. Karulin, M. D. Hesse, M. Tary-Lehmann, and P. V. Lehmann Single-Cytokine-Producing CD4 Memory Cells Predominate in Type 1 and Type 2 Immunity J. Immunol., February 15, 2000; 164(4): 1862 - 1872. [Abstract] [Full Text] [PDF]
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 N. ARAI, H.J. LEE, I. FERBER, H. KURATA, and A. O'GARRA Multiple Levels of Regulation of Th2 Cytokine Gene Expression Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 589 - 598. [Abstract] [PDF]
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L. Yang, L. Cohn, D.-H. Zhang, R. Homer, A. Ray, and P. Ray Essential Role of Nuclear Factor {kappa}B in the Induction of Eosinophilia in Allergic Airway Inflammation J. Exp. Med., November 2, 1998; 188(9): 1739 - 1750. [Abstract] [Full Text] [PDF]
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J. Guo, V. Casolaro, E. Seto, W.-M. Yang, C. Chang, M.-C. Seminario, J. Keen, and S. N. Georas Yin-Yang 1 Activates Interleukin-4 Gene Expression in T Cells J. Biol. Chem., December 21, 2001; 276(52): 48871 - 48878. [Abstract] [Full Text] [PDF]
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