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B and STAT6 in Human Airway Epithelial Cells1
Division of Clinical Immunology and Allergy, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4 in the airway
epithelial cell line, BEAS-2B. Cells were transfected with luciferase
reporter plasmids, which contained up to 1363 bp of the eotaxin
promoter. Eotaxin promoter activity was increased by TNF- (2.5-fold)
and IL-4 (1.5-fold), respectively. The combination of TNF- and IL-4
produced 3.6-fold activation of the eotaxin promoter. The eotaxin
promoter contains overlapping consensus binding sites for transcription
factors, NF-
B and STAT6, which are known to mediate responses to
TNF- and IL-4, respectively. Electrophoretic mobility shift assays
revealed NF-B binding after TNF- stimulation and STAT6 binding
after IL-4 stimulation using a DNA probe derived from the eotaxin
promoter. Mutant plasmids were generated to define the roles of these
transcription factors in eotaxin promoter activity. TNF-
stimulation, but not IL-4 stimulation, was lost in plasmids mutated at
the NF-B binding site, whereas IL-4 stimulation, but not TNF-
stimulation, was lost in plasmids mutated at the STAT6 binding site.
When both sites were mutated, all transcriptional activation was lost.
These results imply that TNF- and IL-4 stimulate expression of the
eotaxin gene by activating NF-B and STAT6. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1 (10). Antigen-induced
up-regulation has been attributed to T cells, especially Th2 cells
(11, 12). Cultured airway epithelial cells have been
reported to express eotaxin (10, 13). Based upon the
preceding, an analysis of the regulation of eotaxin expression in
airway epithelial cells is likely to yield information relevant to the
pathogenesis of allergic inflammation.
Mochizuki et al. (14) reported that TNF- and IL-4
synergistically stimulated eotaxin expression in fibroblasts. We have
found a similar synergistic effect of TNF- and IL-4 in the induction
of eotaxin mRNA and protein expression in airway epithelial cells
(15). Up-regulation of eotaxin expression by TNF- and
IL-4 might be expected to occur in asthma, because TNF- and IL-4 are
both implicated in the pathogenesis of asthma. TNF- is known to be
produced by basophils, mast cells, monocytes, and macrophages
(16, 17). IL-4 is a pivotal cytokine associated with
allergic disease that supports Th2 development and is produced by Th2
cells, basophils, and mast cells (18, 19, 20).
The mechanisms regulating eotaxin expression in airway epithelial cells
are presently unknown. Many putative binding sites for transcription
factors are identified in the eotaxin promoter. Putative binding sites
for NF-B and STAT6 coexist within the proximal region of the eotaxin
promoter. NF-B is a key regulator of immune and inflammatory genes
(21). NF-B is comprised of a homodimer or heterodimer
of Rel family proteins, including NF-B1(p50/p105),
NF-B2(p52/p100), RelA(p65), RelB, and c-Rel. It is sequestered in an
inactive form in the cytoplasm by the inhibitory molecules known as
IB. TNF- activates NF-B by inducing the phosphorylation and
degradation of IB and leads to the translocation of NF-B to the
nucleus where it can bind to specific promoter binding sites
(21). Many cell types are reported to express NF-B,
including airway epithelial cells, and NF-B has been implicated in
epithelial cell responses (22, 23). IL-4 has been shown to
trigger tyrosine phosphorylation of a latent cytoplasmic transcription
factor termed STAT6 via receptor-associated Janus kinase-1
(JAK1)3 and JAK3.
Phosphorylated STAT6 assembles in a dimeric form, translocates into the
nucleus, and trans-activates genes containing specific
regulatory elements (24, 25). Several cell types have been
shown to express STAT6; however, minimal data are available concerning
airway epithelial cells (26).
In the present study we investigated the possible roles of NF-B and
STAT6 in the transcriptional regulation of the eotaxin gene in airway
epithelial cells. We show that overlapping elements for both factors
within the proximal eotaxin promoter mediate the transcriptional
induction of reporter gene constructs by TNF- and IL-4. We also
demonstrate that TNF- activated NF-B and IL-4 activated STAT6 in
airway epithelial cells. These findings provide insight into the
mechanisms of epithelial eotaxin expression in allergic diseases.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BEAS-2B is a human airway epithelial cell line transformed with adenovirus 12-SV40 hybrid virus (a gift from Dr. Curtis Harris) (27). BEAS-2B cells were cultured in Hanks’ F12/DMEM (Biofluids, Rockville, MD) with 10% heat-inactivated FBS, 100 U/ml penicillin, and 100 ng/ml streptomycin (Life Technologies-BRL, Gaithersburg, MD) at 37°C with 5% CO2 in humidified air.
Amplification and cloning of the eotaxin promoter
The promoter region of eotaxin was amplified by the method of Siebert et al. using the Genome Walker kit (Clontech, Palo Alto, CA) (28). The first PCR product was amplified from adaptor-ligated genomic DNA fragments using 5' adaptor primer and a primer derived from the eotaxin exon I sequence (5'-TAGCAGCTGCCTTCAGCCCCCAGGGG-3) (29). The primary PCR reaction mixture was diluted and used as a template for a nested PCR reaction using the nested adaptor primer and the nested primer derived from the eotaxin 5'-upstream sequence (5-ACTTCTGTGGCTGCTGCTCATAG-3). The derived PCR product was cloned using the TA cloning kit (Invitrogen, San Diego, CA), and the construct is referred to as TA-Eotax. Recombinant clones were selected based on PCR screens of derived colonies. Plasmids were isolated using the QIAGEN plasmid purification kit (Qiagen, Santa Clarita, CA). Cloned DNA sequences were determined by the dideoxy method at Johns Hopkins DNA Analysis Facility.
Construction of eotaxin promoter-luciferase reporter plasmids
A 1363-bp fragment of the promoter region of the eotaxin gene (site -1363 to -1) was amplified by PCR using a sense primer containing a restriction site for MluI and an antisense primer containing a restriction site for BglII. The amplified PCR product was cloned into a TA cloning vector and digested with MluI and BglII (New England Biolabs, Beverly, MA). The resulting fragment was cloned into the MluI and BglII sites of a promoterless luciferase reporter pGL3-Basic vector (Promega, Madison, WI), and the construct is referred to as pEotx.1363. The pEotx.478 plasmid was constructed by digesting TA-Eotx.1363 with SacI and BglII and cloning the resulting 478-bp eotaxin promoter fragment into the SacI and BglII sites of the pGL3-Basic vector. The pEotax.300 plasmid was constructed by 5' end digestion of the pEotax.1363 plasmid using exonuclease III and S1 nuclease (Promega). Digested linear vector was circularized by DNA ligase after Klenow DNA polymerase treatment (Promega). The sequence of each plasmid insert DNA was determined by the dideoxy method using the fmol DNA Sequencing System (Promega).
Putative transcription factor binding sites in pEotx.1360 were mutated
using the QuikChange site-directed mutagenesis kit (Stratagene, La
Jolla, CA), using pEotx.1363 as a template. Constructs pEotx.M-1, -2,
and -3 were synthesized by temperature cycling using site-mutated
primers and PfuTurbo DNA polymerase (Stratagene). Nonmutated template
plasmid was digested with DpnI endonuclease (Stratagene).
The mutated plasmid was transformed into XL1-Blue cells (Stratagene)
and purified using the Qiagen plasmid purification kit. Mutations were
selected based on the results of EMSA with mutant probes for each
transcription factor (Table I
). The
sequence of each plasmid was determined by the method mentioned
above.
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BEAS-2B cells were seeded into six-well plates and allowed to grow to 50–70% confluence. Cells were transfected with 3 µl of Fugene 6 transfection reagent (Roche Molecular Biochemicals, Indianapolis, IN) and 1 µg of the plasmids indicated in the text and incubated in 2 ml of medium. Cytokine was added 24 h after transfection. Six hours after cytokine treatment, cells were washed twice with Ca2+- and Mg2+-free HBSS (Life Technologies) and solubilized by incubation in 300 µl of reporter lysis buffer for 15 min (Promega). Cells were transferred to microtubes and centrifuged to pellet cellular debris, and the supernatant was stored at -70°C. Luciferase activity was measured using the Luciferase Assay System (Promega) and a luminometer (Analytic Luminescence Laboratories, Sparks, MD). The protein concentration of the samples was measured using the Bradford protein dye reagent (Bio-Rad, Hercules, CA), and the relative luciferase activity was normalized to the protein concentration.
Electrophoretic mobility shift assays (EMSA)
Nuclear extracts were prepared by the modified method of Schreiber et al. (30). The BEAS-2B cells were stimulated as indicated and then harvested with a scraper after washing twice with HBSS. The cells were washed with buffer A (10 mM HEPES, 15 mM KCl, 2 mM MgCl2, 0.1 mM EDTA, 1 mM DTT, 0.5 mM PMSF, and 10 µg/ml leupeptin; Life Technologies). The cell pellet was resuspended in buffer B (buffer A containing 0.2% Nonidet P-40) and incubated for 2 min. Nuclei were pelleted by centrifugation and resuspended in buffer C (buffer A containing 0.25 M sucrose). Nuclei were again pelleted, then resuspended in buffer D (50 mM HEPES, 400 mM KCl, 10% glycerol, 0.1 mM EDTA, 1 mM DTT, 0.5 mM PMSF, and 10 µg/ml leupeptin) and incubated with shaking for 30 min. All procedures were performed on ice. The mixture was centrifuged, and the supernatant was stored at -70°C.
Whole cell extracts were prepared by modification of a method previously reported (26, 31). Cells were harvested as described above. The cells were resuspended in lysis buffer (20 mM Tris-HCl, 1 mM EDTA, 1 mM DTT, 1% Nonidet P-40, 10% glycerol, 1 mM PMSF, 0.2 mg/ml leupeptin, 1 mM Na3VO4, and 50 mM NaF). Cells were sonicated for 10 s with an ultrasonic cell disrupter (Heat System Ultrasonics, Farmingdale, NY) and then incubated for 5 min. All procedures were performed on ice. Lysates were centrifuged, and the supernatant was collected and stored at -70°C.
DNA-protein binding assays were based on the modified methods
previously reported (31, 32). Aliquots of 5 µg of
nuclear extracts or whole cell extracts were incubated in 10 µl of
total reaction volume containing 10 mM Tris-HCl, 1 mM DTT, 1 mM EDTA,
10% glycerol, 0.1% Triton X-100, 50 µg/ml poly(dI-dC), 0.1 mg/ml
BSA, and 50 mM KCl (Life Technologies) for 5 min with or without
unlabeled oligonucleotide probe. The 32P-labeled
oligonucleotide probe was added to the reaction mixture and then
incubated for 20 min. In some experiments, Abs against p50(NF-B1),
p65(RelA), RelB, c-Rel, p52(NF-B2), STAT1, STAT6 (Santa Cruz
Biotechnology, Santa Cruz, CA), or isotype-matched antisera were
incubated with the mixture for 30 min after incubation with labeled
probe. The reaction products were analyzed by electrophoresis in a 5%
polyacrylamide gel with 0.5 x TBE buffer. The gels were dried and
analyzed by autoradiography. The sequences of the oligonucleotide
probes used are shown in Table I
.
Immunoprecipitation and Western blot
Western blot of nuclear extracts was performed to assess translocation of STAT6 into nuclei as reported previously (33). Fifty micrograms of nuclear extracts or 2 µg of recombinant STAT6 protein (a gift from Dr. Ulrike Schindler) were incubated with 1 µg of anti-STAT6 Ab prebound to protein G-Sepharose beads (Pharmacia Biotech, Piscataway, NJ) for 2 h at 4°C with gentle rotation. After washing three times with the lysis buffer, the immunoprecipitated proteins were boiled for 5 min in the sample buffer containing 0.25 M Tris-HCl, 10% glycerol, 5% SDS, and 0.025% 2-ME (Sigma, St. Louis, MO). The samples were then subjected to 10% Tris-glycine gradient gel electrophoresis (NOVEX, San Diego, CA) and transferred to a nitrocellulose membrane (Amersham, Arlington Heights, IL). The membrane was blocked with 5% nonfat milk powder in TBST (50 mM Tris, 0.15 M NaCl, and 0.05% Tween-20), incubated with 1 µg/ml rabbit anti-STAT6 Ab (Santa Cruz Biotechnology) in TBST for 3 h, washed with TBST, and then incubated with anti-rabbit Ig Ab (Amersham) for 1 h. After extensive washing with TBST, chemiluminescent substrate was added (ECL Western blot detection system, Amersham), and the membrane was subjected to autoradiography.
Statistical analysis
Analyses of data from transfection/luciferase assays were performed using StatView II (Abacus Concepts, Berkeley, CA). Data are expressed as the mean ± SE. Statistical differences were determined by ANOVA with Fisher’s protected least significant difference test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. It contains a
TATA box (at bp -43 to -39) and consensus binding sites for NF-B
(at bp -68 to -59), STAT6 (at bp -74 to -65), AP-1 (at bp -1082 to
-1076), and C/EBP (at bp -1278 to -1270). The overall sequence is
similar, but not identical, to those published by Garcia-Zepeda et al.
and Hein et al. (34, 35). This fragment was cloned into a
luciferase reporter plasmid for further functional analysis.
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(0.1, 1, 10, and 100 ng/ml) dose dependently increased
luciferase activity in BEAS-2B cells transfected with the pEotx.1363
plasmid (Fig. 2A). Maximum
induction was observed using 100 ng/ml of TNF- (2.5 ±
0.1-fold; p < 0.05 compared with control). IL-4 (0.5,
5, and 50 ng/ml) also increased luciferase activity dose dependently,
although modestly compared with TNF- (Fig. 2B). Maximum
induction was observed using 50 ng/ml of IL-4 (1.5 ± 0.04-fold;
p < 0.05 compared with control). The combination of
100 ng/ml TNF- and 50 ng/ml IL-4 additively activated the eotaxin
promoter (3.6 ± 0.2-fold; p < 0.05 compared with
control; Fig. 3A). Similar
results were obtained using cells transfected with reporter plasmids
containing either a 478-bp fragment or a 300-bp fragment of the eotaxin
promoter (Fig. 3, B and C).
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are known to be mediated via activation of
NF-B, while IL-4 is known to activate STAT6 via JAK1 and JAK3. We
therefore used EMSA to determine whether stimulation with these
cytokines results in formation of active NF-B or STAT6. EMSA with
nuclear extracts from BEAS-2B cells stimulated with 10 ng/ml TNF-
resulted in the formation of a strong binding complex (complex 1) using
a DNA probe spanning the putative binding sites for STAT6 and NF-B
in the eotaxin promoter (Fig. 4A). This binding complex was
blocked or supershifted by Abs to p50 and p65 NF-B Rel family
members. Abs against other Rel family members (RelB, c-Rel, and p52)
and STAT6 did not affect formation of the binding complex. Preimmune
rabbit and goat IgG did not influence complex formation (data not
shown). The binding specificity of the NF-B complex was further
assessed by competition with unlabeled oligonucleotides. Unlabeled
wild-type oligonucleotide and an oligonucleotide only mutated within
the putative STAT6 binding site (referred to as m1, Table I) competed
for DNA-protein complex formation (Fig. 4B), while two
oligonucleotides carrying a mutation within the putative NF-B
binding site (referred to as m2 and m3) were ineffective. Taken
together, these results suggest that TNF- induces the formation of a
sequence-specific NF-B complex composed of p65/p50 heterodimers.
IL-4 did not induce NF-B and the combination of IL-4 and TNF- did
not alter the binding complex compared with TNF- alone (data not
shown). An unknown complex (complex 2) was formed equally in
unstimulated cells or cells stimulated with TNF- (Fig. 4, A and B). Although this constitutive complex was
not inhibited by any of the Ab mentioned above (Fig. 4A),
the complex formation was inhibited by excess of wild-type
oligonucleotide and m1 (Fig. 4B).
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B. Therefore, we confirmed the
ability of DNA-STAT6 binding by following experiments based on the
method described by Guo et al. (26), because activated
STAT6 in cytoplasm can be bound to DNA probe. EMSA with whole cell
extracts from BEAS-2B cells stimulated with 10 ng/ml IL-4 were
performed. A binding complex (complex 1) was induced by IL-4 and
detectable in whole cell extracts using a wild-type DNA probe (Fig. 5). This binding complex was confirmed to
contain STAT6 by inhibition using anti-STAT6 Ab. Abs against Rel
family members and STAT1 did not influence formation of the binding
complex (Fig. 5), nor did rabbit IgG (data not shown). Unlabeled
wild-type oligonucleotide and the oligonucleotide mutated at only the
NF-B binding site (m2) inhibited DNA-protein binding, while
oligonucleotides mutated at the STAT6 binding site (m1 and m3) were
inactive. TNF- did not induce STAT6, and the combination of IL-4 and
TNF- did not alter the STAT6-DNA binding complex compared with IL-4
alone (data not shown). Unknown complexes 2, 3, and 4 seem to be
comprised of constitutively expressed proteins that bound to the
eotaxin promoter. Taken together, these results indicate that IL-4
induces activation of functional STAT6 in airway epithelial cells.
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). The amount of STAT6 in the nucleus
increased after stimulation with IL-4.
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B and STAT6 binding sites in transcription
of the eotaxin gene, luciferase reporter plasmids with mutated proximal
promoters were used. The sequences of sites in the mutant plasmids are
shown in Table I. A reporter using the eotaxin promoter mutated at the
binding site for STAT6 (referred to as pEotx.M1) showed total loss of
IL-4 stimulation (Fig. 7B) and
an additive effect with TNF-, but still responded to stimulation
with TNF-. A reporter plasmid, pEotx.M2, which was mutated at the
binding site of NF-B, showed total loss of TNF- stimulation and
additive activation with IL-4 (Fig. 7C), but still responded
to stimulation with IL-4. Neither TNF- nor IL-4 activated the
reporter, pEotx.M3, which was mutated at the overlapping binding sites
for STAT6 and NF-B (Fig. 7D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4. Combining these two cytokines caused an additive
effect. Alone, TNF- was a stronger stimulus than IL-4. Because a
strong synergy between these two stimuli is observed at the protein
level, and an intermediate synergy is observed in Northern blot
studies, we suspect that post-transcriptional and/or translational
mechanisms may be involved (15). Based upon the presence
of a single site containing overlapping consensus response elements for
both NF-B and STAT6, we used EMSA to probe for activation of these
two transcription factors. NF-B has been known to regulate
expression of several inflammatory proteins, including RANTES, IL-8,
monocyte chemoattractant protein-1, inducible nitric oxide synthase,
VCAM-1, and ICAM-1 (23, 36, 37, 38, 39, 40). STAT6 has been shown to
be essential for most responses to IL-4. It activates transcription of
several IL-4-induced genes, such as CD23 (the low affinity IgE
receptor), MHC class II, and IgE germline and mediates Th2 development
(24, 41, 42, 43).
TNF- induced the activation of NF-B, which bound to a DNA probe
derived from the eotaxin proximal promoter in airway epithelial cells.
The sequence of this site is slightly different from a consensus
sequence of the NF-B binding site (the consensus sequence is
GGGRNNYYCC; the eotaxin promoter sequence is GGAATCTCCC;
positions bp -68 to -59; N indicates any of nucleotides, R indicates
A or G, and Y indicates C or T; see Table I) (21, 44). The
proteins bound to the DNA probe were confirmed to be p50 and p65 of the
NF-B family, however, using specific Abs.
Activation of STAT6 by IL-4 was detected by EMSA using a DNA probe
derived from the eotaxin promoter that contains a putative STAT6
binding site (the consensus sequence is TTCN3/4 GAA; the eotaxin
sequence is TTCCCTGGAA; positions bp -74 to -65; see Table I)
(45) and also overlaps with the 5'-end of the putative
NF-B binding site mentioned above. The specificity of
TNF--induced NF-B and IL-4-induced STAT6 was further established
by the ability of unlabeled consensus probes to inhibit respective
complex formation as well as by the use of unlabeled eotaxin probe
mutated at either site. Thus, we have identified a unique site in the
eotaxin promoter that binds to both NF-B and STAT6. Other
investigators have reported that TNF- can induce or enhance STAT6
activation, and IL-4 can induce activation of NF-B
(46, 47, 48); however, our results suggest that TNF-
activated NF-B and not STAT6, while IL-4 activated STAT6 and not
NF-B. Both these transcription factors independently bound to the
eotaxin promoter element in our studies.
Having established that TNF- and IL-4 can activate eotaxin promoter
reporter plasmids, and that TNF- activated NF-B and IL-4
activated STAT6, we next tested whether NF-B and STAT6 were
responsible for activating the reporter genes. Promoter assays using
mutant plasmids showed that the putative NF-B site at -68 to -59
is necessary for TNF- activation of the eotaxin promoter. Likewise,
results with the pEotx.M1 mutant indicate that the putative STAT6
binding site was necessary for IL-4 activation of the promoter. In both
cases, the additive effects were lost when plasmids mutated at either
site were used. These findings add support to the data from EMSA,
suggesting that TNF- and IL-4 activate the eotaxin promoter via
NF-B and STAT6, respectively.
TNF- has been shown to activate NF-IL-6 (C/EBP family) and AP-1
(49, 50). Our eotaxin reporter plasmid contains consensus
binding sites for both these factors as has been indicated by other
investigators (34, 35). We did not detect any clear
complexes from EMSA using DNA probes derived from these sequences after
TNF- treatment, however (data not shown). Although IL-4 has also
been reported to activate the C/EBP family (51), no clear
DNA-protein binding was observed in EMSA with a probe derived from the
C/EBP consensus element contained in the eotaxin promoter (data not
shown). Reporter gene assays using further truncated forms of the
promoter (pEotx.478 and pEotx.300) recapitulated the findings with the
1363-bp promoter fragment. Because activation by TNF- and IL-4 was
preserved in the transfections with these plasmids that do not contain
the putative binding sites for C/EBP or AP-1, these transcription
factors are not likely to be essential for activation of the eotaxin
promoter fragments used by TNF- and IL-4.
The results of this study suggest that NF-B and STAT6 act positively
at a site on the eotaxin promoter containing overlapping binding sites.
This contrasts with the results of Bennet et al., who reported
suppression of TNF-stimulated E-selectin expression by STAT6 antagonism
of NF-B (52). They suggested that overlapping binding
sites of NF-B and STAT6 in the E-selectin promoter resulted in
competition between STAT6 and NF-B for binding. On the E-selectin
promoter, there are two adjacent, but nonoverlapping, binding sites for
NF-B that are straddled by a STAT6 binding site that shares 5 bp
with each NF-B site. In the eotaxin promoter, STAT6 and NF-B
share only 4 bp for both factors; this structure may make it possible
for factors to bind simultaneously to the overlapping site on the
eotaxin promoter. Shen et al. and Iciek et al. have reported that
NF-B and STAT6 synergistically activate the mouse germline C
promoter (48, 53). A similar mechanism has been reported
in the human IgE germline promoter (54). In these cases, a
STAT6 binding site was adjacent to a NF-B binding site, although
these sites were separated by several nucleotides. There are other
reports that support an cooperation between NF-B and STAT6 on
overlapping binding sites. Isalan et al. demonstrated that zinc
finger-containing proteins can generally recognize overlapping DNA
binding domains based upon analysis of the crystal structure of these
binding proteins (55). Although the three-dimensional
crystal structures of STATs and NF-B have been analyzed (44, 56), there are few data concerning such interactions of these
two transcription factor families. Wotton et al. reported cooperative
binding of Ets-1 and core binding factor to the individual sites, which
are directly adjacent on the TCR ß gene enhancer region of the
promoter (57). Our mutagenesis experiments clearly
establish independent roles for NF-B and STAT6 in regulating the
eotaxin promoter despite the intimate association of binding sites for
these two factors. These reports and our data suggest that the
differences in DNA motif and structure of promoter could result in
different patterns of protein binding to DNA and promoter activity.
Further study will be necessary to better understand the mechanism of
interactions of NF-B and STAT6 on the eotaxin promoter, especially
in mediation of the synergy between TNF- and IL-4.
Both NF-B and STAT6 have been implicated in allergic inflammation.
Yang et al. have shown that mice deficient in the p50 subunit of
NF-B protein do not mount eosinophilic lung inflammation and that
eotaxin expression was inhibited compared with that in wild-type mice
(58). Their data are in agreement with our findings
indicating an important role for NF-B in the regulation of eotaxin
in airway epithelium. Airway eosinophilia and hypersensitivity were
severely reduced in STAT6-deficient mice (59, 60). This
could result from impaired Th2 development or IgE synthesis, which are
mainly regulated by IL-4/STAT6. Our studies suggest that impaired
eotaxin synthesis in STAT6-deficient mice may be expected to contribute
to reduced eosinophil infiltration.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert P. Schleimer, Johns Hopkins Asthma and Allergy Center, Room 3A.62, 5501 Hopkins Bayview Circle, Baltimore, MD 21224-6801. E-mail address:
3 Abbreviation used in this paper: JAK, Janus kinase.
Received for publication May 27, 1999. Accepted for publication September 22, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R. Ahrens, A. Waddell, L. Seidu, C. Blanchard, R. Carey, E. Forbes, M. Lampinen, T. Wilson, E. Cohen, K. Stringer, et al. Intestinal Macrophage/Epithelial Cell-Derived CCL11/Eotaxin-1 Mediates Eosinophil Recruitment and Function in Pediatric Ulcerative Colitis J. Immunol., November 15, 2008; 181(10): 7390 - 7399. [Abstract] [Full Text] [PDF]
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 C. A. Hudson, G. P. Christophi, R. C. Gruber, J. R. Wilmore, D. A. Lawrence, and P. T. Massa Induction of IL-33 expression and activity in central nervous system glia J. Leukoc. Biol., September 1, 2008; 84(3): 631 - 643. [Abstract] [Full Text] [PDF]
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 M. Nonaka, N. Ogihara, A. Fukumoto, A. Sakanushi, R. Pawankar, and T. Yagi Combined Stimulation of Nasal Polyp Fibroblasts With Poly IC, Interleukin 4, and Tumor Necrosis Factor {alpha} Potently Induces Production of Thymus- and Activation-Regulated Chemokine Arch Otolaryngol Head Neck Surg, June 1, 2008; 134(6): 630 - 635. [Abstract] [Full Text] [PDF]
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A. Kato, S. Favoreto Jr., P. C. Avila, and R. P. Schleimer TLR3- and Th2 Cytokine-Dependent Production of Thymic Stromal Lymphopoietin in Human Airway Epithelial Cells J. Immunol., July 15, 2007; 179(2): 1080 - 1087. [Abstract] [Full Text] [PDF]
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H. Novak, A. Muller, N. Harrer, C. Gunther, J. M. Carballido, and M. Woisetschlager CCL23 Expression Is Induced by IL-4 in a STAT6-Dependent Fashion J. Immunol., April 1, 2007; 178(7): 4335 - 4341. [Abstract] [Full Text] [PDF]
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D. R. Dorscheid, B. J. Patchell, O. Estrada, B. Marroquin, R. Tse, and S. R. White Effects of corticosteroid-induced apoptosis on airway epithelial wound closure in vitro Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L794 - L801. [Abstract] [Full Text] [PDF]
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 Y. Miyazaki, T. Satoh, K. Nishioka, and H. Yokozeki STAT-6-Mediated Control of P-Selectin by Substance P and Interleukin-4 in Human Dermal Endothelial Cells Am. J. Pathol., August 1, 2006; 169(2): 697 - 707. [Abstract] [Full Text] [PDF]
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D. K. Fritz, C. Kerr, L. Tong, D. Smyth, and C. D. Richards Oncostatin-M Up-Regulates VCAM-1 and Synergizes with IL-4 in Eotaxin Expression: Involvement of STAT6 J. Immunol., April 1, 2006; 176(7): 4352 - 4360. [Abstract] [Full Text] [PDF]
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 D. H. Broide, T. Lawrence, T. Doherty, J. Y. Cho, M. Miller, K. McElwain, S. McElwain, and M. Karin Allergen-induced peribronchial fibrosis and mucus production mediated by I{kappa}B kinase {beta}-dependent genes in airway epithelium PNAS, December 6, 2005; 102(49): 17723 - 17728. [Abstract] [Full Text] [PDF]
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A. Lehtonen, V. Veckman, T. Nikula, R. Lahesmaa, L. Kinnunen, S. Matikainen, and I. Julkunen Differential Expression of IFN Regulatory Factor 4 Gene in Human Monocyte-Derived Dendritic Cells and Macrophages J. Immunol., November 15, 2005; 175(10): 6570 - 6579. [Abstract] [Full Text] [PDF]
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 J. Fan, N. M. Heller, M. Gorospe, U. Atasoy, and C. Stellato The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy Eur. Respir. J., November 1, 2005; 26(5): 933 - 947. [Abstract] [Full Text] [PDF]
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 K. Minamoto, H. Harada, V. N. Lama, M. A. Fedarau, and D. J. Pinsky Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase J. Exp. Med., July 18, 2005; 202(2): 283 - 294. [Abstract] [Full Text] [PDF]
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M. Nie, A. J. Knox, and L. Pang {beta}2-Adrenoceptor Agonists, Like Glucocorticoids, Repress Eotaxin Gene Transcription by Selective Inhibition of Histone H4 Acetylation J. Immunol., July 1, 2005; 175(1): 478 - 486. [Abstract] [Full Text] [PDF]
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S. M. Pope, P. C. Fulkerson, C. Blanchard, H. S. Akei, N. M. Nikolaidis, N. Zimmermann, J. D. Molkentin, and M. E. Rothenberg Identification of a Cooperative Mechanism Involving Interleukin-13 and Eotaxin-2 in Experimental Allergic Lung Inflammation J. Biol. Chem., April 8, 2005; 280(14): 13952 - 13961. [Abstract] [Full Text] [PDF]
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H. S. Chang, J. S. Kim, J. H. Lee, J. I. Cho, T. Y. Rhim, S.-T. Uh, B. L. Park, I. Y. Chung, C.-S. Park, and H. D. Shin A Single Nucleotide Polymorphism on the Promoter of eotaxin1 Associates with Its mRNA Expression and Asthma Phenotypes J. Immunol., February 1, 2005; 174(3): 1525 - 1531. [Abstract] [Full Text] [PDF]
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M. Nie, L. Corbett, A. J. Knox, and L. Pang Differential Regulation of Chemokine Expression by Peroxisome Proliferator-activated Receptor {gamma} Agonists: INTERACTIONS WITH GLUCOCORTICOIDS AND {beta}2-AGONISTS J. Biol. Chem., January 28, 2005; 280(4): 2550 - 2561. [Abstract] [Full Text] [PDF]
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 C. Stellato Post-transcriptional and Nongenomic Effects of Glucocorticoids Proceedings of the ATS, November 1, 2004; 1(3): 255 - 263. [Abstract] [Full Text] [PDF]
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 N. M. Heller, S. Matsukura, S. N. Georas, M. R. Boothby, P. B. Rothman, C. Stellato, and R. P. Schleimer Interferon-{gamma} Inhibits STAT6 Signal Transduction and Gene Expression in Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., November 1, 2004; 31(5): 573 - 582. [Abstract] [Full Text] [PDF]
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C. Desmet, P. Gosset, B. Pajak, D. Cataldo, M. Bentires-Alj, P. Lekeux, and F. Bureau Selective Blockade of NF-{kappa}B Activity in Airway Immune Cells Inhibits the Effector Phase of Experimental Asthma J. Immunol., November 1, 2004; 173(9): 5766 - 5775. [Abstract] [Full Text] [PDF]
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 A. Hoshino, T. Tsuji, J. Matsuzaki, T. Jinushi, S. Ashino, T. Teramura, K. Chamoto, Y. Tanaka, Y. Asakura, T. Sakurai, et al. STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation Int. Immunol., October 1, 2004; 16(10): 1497 - 1505. [Abstract] [Full Text] [PDF]
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K. Takamura, Y. Nasuhara, M. Kobayashi, T. Betsuyaku, Y. Tanino, I. Kinoshita, E. Yamaguchi, S. Matsukura, R. P. Schleimer, and M. Nishimura Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L777 - L785. [Abstract] [Full Text] [PDF]
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 Q. Peng, T. Matsuda, and S. J. Hirst Signaling Pathways Regulating Interleukin-13-stimulated Chemokine Release from Airway Smooth Muscle Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 596 - 603. [Abstract] [Full Text] [PDF]
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U. Atasoy, S. L. Curry, I. Lopez de Silanes, A.-B. Shyu, V. Casolaro, M. Gorospe, and C. Stellato Regulation of Eotaxin Gene Expression by TNF-{alpha} and IL-4 Through mRNA Stabilization: Involvement of the RNA-Binding Protein HuR J. Immunol., October 15, 2003; 171(8): 4369 - 4378. [Abstract] [Full Text] [PDF]
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Z. Chen, R. Lund, T. Aittokallio, M. Kosonen, O. Nevalainen, and R. Lahesmaa Identification of Novel IL-4/Stat6-Regulated Genes in T Lymphocytes J. Immunol., October 1, 2003; 171(7): 3627 - 3635. [Abstract] [Full Text] [PDF]
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D. S. Faffe, T. Whitehead, P. E. Moore, S. Baraldo, L. Flynt, K. Bourgeois, R. A. Panettieri, and S. A. Shore IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L907 - L914. [Abstract] [Full Text] [PDF]
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M. Richter, A. M. Cantin, C. Beaulieu, A. Cloutier, and P. Larivee Zinc chelators inhibit eotaxin, RANTES, and MCP-1 production in stimulated human airway epithelium and fibroblasts Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L719 - L729. [Abstract] [Full Text] [PDF]
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K. Honda, M. Arima, G. Cheng, S. Taki, H. Hirata, F. Eda, F. Fukushima, B. Yamaguchi, M. Hatano, T. Tokuhisa, et al. Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine J. Exp. Med., August 18, 2003; 198(4): 533 - 543. [Abstract] [Full Text] [PDF]
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H. Takizawa, S. Abe, H. Okazaki, T. Kohyama, I. Sugawara, Y. Saito, T. Ohtoshi, S. Kawasaki, M. Desaki, K. Nakahara, et al. Diesel exhaust particles upregulate eotaxin gene expression in human bronchial epithelial cells via nuclear factor-kappa B-dependent pathway Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L1055 - L1062. [Abstract] [Full Text] [PDF]
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K. Chibana, Y. Ishii, T. Asakura, and T. Fukuda Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin J. Immunol., April 15, 2003; 170(8): 4290 - 4295. [Abstract] [Full Text] [PDF]
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A. M. Stutz, L. A. Pickart, A. Trifilieff, T. Baumruker, E. Prieschl-Strassmayr, and M. Woisetschlager The Th2 Cell Cytokines IL-4 and IL-13 Regulate Found in Inflammatory Zone 1/Resistin-Like Molecule {alpha} Gene Expression by a STAT6 and CCAAT/Enhancer-Binding Protein-Dependent Mechanism J. Immunol., February 15, 2003; 170(4): 1789 - 1796. [Abstract] [Full Text] [PDF]
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J. Mattes, M. Hulett, W. Xie, S. Hogan, M. E. Rothenberg, P. Foster, and C. Parish Immunotherapy of Cytotoxic T Cell-resistant Tumors by T Helper 2 Cells: An Eotaxin and STAT6-dependent Process J. Exp. Med., February 3, 2003; 197(3): 387 - 393. [Abstract] [Full Text] [PDF]
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C. Langdon, C. Kerr, L. Tong, and C. D. Richards Oncostatin M Regulates Eotaxin Expression in Fibroblasts and Eosinophilic Inflammation in C57BL/6 Mice J. Immunol., January 1, 2003; 170(1): 548 - 555. [Abstract] [Full Text] [PDF]
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D.-w. Jeong, M.-H. Yoo, T. S. Kim, J.-H. Kim, and I. Y. Kim Protection of Mice from Allergen-induced Asthma by Selenite. PREVENTION OF EOSINOPHIL INFILTRATION BY INHIBITION OF NF-kappa B ACTIVATION J. Biol. Chem., May 10, 2002; 277(20): 17871 - 17876. [Abstract] [Full Text] [PDF]
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S. J. Hirst, M. P. Hallsworth, Q. Peng, and T. H. Lee Selective Induction of Eotaxin Release by Interleukin-13 or Interleukin-4 in Human Airway Smooth Muscle Cells Is Synergistic with Interleukin-1beta and Is Mediated by the Interleukin-4 Receptor alpha -Chain Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1161 - 1171. [Abstract] [Full Text] [PDF]
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S. N. Georas, L. A. Beck, and C. Stellato What Is Eotaxin Doing in the Pleura? . Insights into Innate Immunity from Pleural Mesothelial Cells Am. J. Respir. Cell Mol. Biol., April 1, 2002; 26(4): 384 - 387. [Full Text] [PDF]
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M. E. Poynter, C. G. Irvin, and Y. M. W. Janssen-Heininger Rapid Activation of Nuclear Factor-{kappa}B in Airway Epithelium in a Murine Model of Allergic Airway Inflammation Am. J. Pathol., April 1, 2002; 160(4): 1325 - 1334. [Abstract] [Full Text] [PDF]
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M. Relloso, A. Puig-Kroger, O. M. Pello, J. L. Rodriguez-Fernandez, G. de la Rosa, N. Longo, J. Navarro, M. A. Munoz-Fernandez, P. Sanchez-Mateos, and A. L. Corbi DC-SIGN (CD209) Expression Is IL-4 Dependent and Is Negatively Regulated by IFN, TGF-{beta}, and Anti-Inflammatory Agents J. Immunol., March 15, 2002; 168(6): 2634 - 2643. [Abstract] [Full Text] [PDF]
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K. Blease, J. M. Schuh, C. Jakubzick, N. W. Lukacs, S. L. Kunkel, B. H. Joshi, R. K. Puri, M. H. Kaplan, and C. M. Hogaboam Stat6-Deficient Mice Develop Airway Hyperresponsiveness and Peribronchial Fibrosis during Chronic Fungal Asthma Am. J. Pathol., February 1, 2002; 160(2): 481 - 490. [Abstract] [Full Text] [PDF]
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P. Delmotte, S. Degroote, J.-J. Lafitte, G. Lamblin, J.-M. Perini, and P. Roussel Tumor Necrosis Factor alpha Increases the Expression of Glycosyltransferases and Sulfotransferases Responsible for the Biosynthesis of Sialylated and/or Sulfated Lewis x Epitopes in the Human Bronchial Mucosa J. Biol. Chem., January 4, 2002; 277(1): 424 - 431. [Abstract] [Full Text]
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 K. Fukuda, Y. Fujitsu, N. Kumagai, and T. Nishida Characterization of the Interleukin-4 Receptor Complex in Human Corneal Fibroblasts Invest. Ophthalmol. Vis. Sci., January 1, 2002; 43(1): 183 - 188. [Abstract] [Full Text] [PDF]
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H. Nakamura, A. D. Luster, H. Tateno, S. Jedrzkiewicz, G. Tamura, K. J. Haley, E. A. Garcia-Zepeda, K. Yamaguchi, and C. M. Lilly IL-4 differentially regulates eotaxin and MCP-4 in lung epithelium and circulating mononuclear cells Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1288 - L1302. [Abstract] [Full Text] [PDF]
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S. Fujiie, K. Hieshima, D. Izawa, T. Nakayama, R. Fujisawa, H. Ohyanagi, and O. Yoshie Proinflammatory cytokines induce liver and activation-regulated chemokine/macrophage inflammatory protein-3{alpha}/CCL20 in mucosal epithelial cells through NF-{kappa}B Int. Immunol., October 1, 2001; 13(10): 1255 - 1263. [Abstract] [Full Text] [PDF]
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J. Hoeck and M. Woisetschlager Activation of Eotaxin-3/CCL26 Gene Expression in Human Dermal Fibroblasts Is Mediated by STAT6 J. Immunol., September 15, 2001; 167(6): 3216 - 3222. [Abstract] [Full Text] [PDF]
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J. Mattes, M. Yang, A. Siqueira, K. Clark, J. MacKenzie, A. N. J. McKenzie, D. C. Webb, K. I. Matthaei, and P. S. Foster IL-13 Induces Airways Hyperreactivity Independently of the IL-4R{alpha} Chain in the Allergic Lung J. Immunol., August 1, 2001; 167(3): 1683 - 1692. [Abstract] [Full Text] [PDF]
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M. Afanasyeva, Y. Wang, Z. Kaya, S. Park, M. J. Zilliox, B. H. Schofield, S. L. Hill, and N. R. Rose Experimental Autoimmune Myocarditis in A/J mice Is an Interleukin-4-Dependent Disease with a Th2 Phenotype Am. J. Pathol., July 1, 2001; 159(1): 193 - 203. [Abstract] [Full Text] [PDF]
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S. Matsukura, C. Stellato, S. N. Georas, V. Casolaro, J. R. Plitt, K. Miura, S. Kurosawa, U. Schindler, and R. P. Schleimer Interleukin-13 Upregulates Eotaxin Expression in Airway Epithelial Cells by a STAT6-Dependent Mechanism Am. J. Respir. Cell Mol. Biol., June 1, 2001; 24(6): 755 - 761. [Abstract] [Full Text] [PDF]
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A. Mathew, J. A. MacLean, E. DeHaan, A. M. Tager, F. H.Y. Green, and A. D. Luster Signal Transducer and Activator of Transcription 6 Controls Chemokine Production and T Helper Cell Type 2 Cell Trafficking in Allergic Pulmonary Inflammation J. Exp. Med., May 7, 2001; 193(9): 1087 - 1096. [Abstract] [Full Text] [PDF]
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J. Hoeck and M. Woisetschlager STAT6 Mediates Eotaxin-1 Expression in IL-4 or TNF-{{alpha}}-Induced Fibroblasts J. Immunol., April 1, 2001; 166(7): 4507 - 4515. [Abstract] [Full Text] [PDF]
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S. Jedrzkiewicz, H. Nakamura, E. S. Silverman, A. D. Luster, N. Mansharamani, K. H. In, G. Tamura, and C. M. Lilly IL-1beta induces eotaxin gene transcription in A549 airway epithelial cells through NF-kappa B Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1058 - L1065. [Abstract] [Full Text] [PDF]
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G. B. Ehret, P. Reichenbach, U. Schindler, C. M. Horvath, S. Fritz, M. Nabholz, and P. Bucher DNA Binding Specificity of Different STAT Proteins. COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES J. Biol. Chem., February 23, 2001; 276(9): 6675 - 6688. [Abstract] [Full Text] [PDF]
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R. H. Harrington and A. Sharma Transcription Factors Recognizing Overlapping C1-A2 Binding Sites Positively Regulate Insulin Gene Expression J. Biol. Chem., January 5, 2001; 276(1): 104 - 113. [Abstract] [Full Text] [PDF]
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A. M. Stutz, J. Hoeck, F. Natt, B. Cuenoud, and M. Woisetschlager Inhibition of Interleukin-4- and CD40-induced IgE Germline Gene Promoter Activity by 2'-Aminoethoxy-modified Triplex-forming Oligonucleotides J. Biol. Chem., April 6, 2001; 276(15): 11759 - 11765. [Abstract] [Full Text] [PDF]
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M. A. Huber, A. Denk, R. U. Peter, L. Weber, N. Kraut, and T. Wirth The IKK-2/Ikappa Balpha /NF-kappa B Pathway Plays a Key Role in the Regulation of CCR3 and eotaxin-1 in Fibroblasts. A CRITICAL LINK TO DERMATITIS IN Ikappa Balpha -DEFICIENT MICE J. Biol. Chem., January 4, 2002; 277(2): 1268 - 1275. [Abstract] [Full Text] [PDF]
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P. E. Moore, T. L. Church, D. D. Chism, R. A. Panettieri Jr., and S. A. Shore IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L847 - L853. [Abstract] [Full Text] [PDF]
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