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*
Department of Immunology IMM-25, Scripps Research Institute, La Jolla, CA 92037; and
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and KC; IL-4 also increased the production of
monocyte-chemotactic protein-1; IL-13 and IL-4 induced eotaxin. IL-13
was by far the most potent inducer of eotaxin; indeed, a neutralizing
anti-IL-13 Ab removed most of the eotaxin-inducing activity from
Th2 supernatants, although it did not entirely block the recruitment of
eosinophils. While TNF- did not stimulate eotaxin production by
itself, it markedly augmented eotaxin induction by IL-13. IL-13 was
able to induce eotaxin in the lung of JAK3-deficient mice, suggesting
that JAK3 is not required for IL-13 signaling in airway epithelial
cells; however, eosinophilia was not induced in this situation,
suggesting that JAK3 transduces other IL-13-mediated mechanisms
critical for eosinophil recruitment. Our study suggests that IL-13 is
an important mediator in the pathogenesis of asthma and therefore a
potential target for asthma therapy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1),3
monocyte-chemotactic protein-3 (MCP-3), and MCP-5 7, 8 . Furthermore,
the recently characterized C-C chemokine eotaxin was the major
eosinophil chemoattractant found in bronchoalveolar lavage (BAL) fluid
from rodent models of allergic inflammation 9, 10 and was also
up-regulated in BAL of asthma patients 11 . The selective recruitment
of eosinophils by eotaxin suggests that this chemokine is crucial in
asthma inflammation.
In vitro studies have shown that chemokines involved in asthma are
regulated by certain cytokines. Thus, RANTES produced by human airway
muscle cells is stimulated by TNF- plus IFN-
but inhibited by
IL-4, IL-10, and IL-13 12 . Eotaxin expression by human dermal
fibroblasts 13 and lung epithelial cells 14 was stimulated by
IFN- in the presence of IL-1 and TNF-, while eotaxin produced by
human fibroblasts was induced by IL-4 15 . Th2 cytokines have been
implicated as playing a central role in eosinophil recruitment in
murine models of allergic asthma, and adoptively transferred Th2 cells
induced eotaxin expression in the lung as well as a lung eosinophilia
16, 17, 18 . We therefore sought to examine the notion that while Th2
cytokines stimulate the growth and activation of eosinophils, they may
also stimulate the production of eosinophil chemoattractants in the
lung during asthma responses.
In this study, we tested the effects of Th2 supernatant and some individual Th2 cytokines, IL-3, IL-4, IL-5, and IL-13, on chemokine production in the lung. We found that Th2 supernatant significantly induced the expression of eotaxin as well as RANTES, MCP-1, and KC in the lung. Individual cytokines showed different abilities to up-regulate expression of the various chemokines; interestingly, IL-13 was the most potent inducer of eotaxin expression at both the mRNA and protein levels, with lung expression mainly in epithelial cells. The induction of eotaxin was found to be Janus family kinase-3 (JAK3) independent, although eosinophilia remained JAK3 dependent.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR-SFE x BALB/c transgenic mice were previously described 19 . These mice are transgenic for a TCR specific for influenza PR8 hemagglutinin peptide 110–119 (SFERFEIFPK) presented on I-Ed. Naive BALB/cByJ (referred to as BALB/c) and BALB/cByJSmn-Prkdcscid/J (referred to as SCID) mice (6–8 wk) were provided by the Rodent Breeding Colony in The Scripps Research Institute (TSRI). JAK3-/- mice 20 were obtained from Dr. L. Berg. All mice were maintained in the TSRI rodent colony, in accordance with National Institutes of Health and TSRI institutional guidelines.
Cytokines and Abs
Murine rIL-2, rIL-3, rIL-4, and rTNF- were purchased from
Pepro Tech (Rocky Hill, NJ), rIL-5 was purchased from PharMingen (San
Diego, CA), rIL-12 was purchased from Genzyme (Cambridge, MA), and the
rIL-13 used in this study was produced by a stably transfected BW5147
cell line and assayed as previously described 21 . Anti-IL-12 was a
monoclonal rat IgG, clone C17.8.20 (kind gift of Dr. G. Trinchieri).
The goat anti-mouse IL-13 polyclonal Ab was purchased from R&D
Systems (Minneapolis, MN) and required 1 µg to neutralize 10 ng of
IL-13. The goat anti-mouse eotaxin polyclonal Ab was also purchased
from R&D. The coding region of murine eotaxin (GenBank accession no.
U77462) without signal peptide was generated by PCR, subcloned into
pETM1, and expressed in Escherichia coli. The recombinant
eotaxin was purified by a affinity chromatography using a
nickel-nitrilotriacetic acid column and was refolded on the
column as described previously 22 . Anti-CD4 and Mel-14 (CD62L) were
purchased from PharMingen.
Generation of Th1 and Th2 supernatant
Th1 and Th2 cells were generated from naive lymph node T cells
(sorted CD4+ Mel-14high) from TCR-SFE x
BALB/c mice. T cells (106) were cultured with 5 x
106 irradiated (2500 rad) spleen cells with 0.5 µg/ml SFE
peptide under conditions driving development of Th1 (20 ng/ml IL-12) or
Th2 (25 ng/ml IL-4 plus 100 µg/ml anti-IL-12). Media was changed
every 2–3 days, and from day 3 on, 50 U/ml of IL-2 were added to all
cultures. Day 5 Th1 or Th2 cells (3 x 106/ml) were
stimulated with Con A (5 µg/ml, Sigma, St. Louis, MO) for 24 h,
and supernatants were collected and treated with 20 mM
methyl--D-mannopyranoside to bind Con A. Cytokines in
the supernatants were tested by ELISA (IL-3, IL-4, IL-5, IL-10,
granulocyte-macrophage CSF (GM-CSF), and IFN-, PharMingen; IL-13 and
TNF-, R&D Systems).
Treatment of mice with T cell supernatant or cytokines
Recombinant murine (rm) IL-3, rmIL-4, rmIL-5, rmIL-13, and
rmTNF- (concentration indicated) were administered to naive BALB/c
mice (50 µl intranasally) three times a day for 2.5 days. In the case
of anti-IL-13 blocking, anti-IL-13 or control Ab was added to
Th2 supernatant 1 h before use. Mice were killed 3 h after
the last treatment, and their lungs were perfused from the right
ventricle using PBS until they had turned white; BAL was collected by
washing the lung through the trachea three times using 1 ml of RPMI
with 2% horse serum. Cytospins were prepared for BAL cells from each
mouse. The right lobes of the lung were then frozen in Trizol reagent
(Life Technologies, Grand Island, NY) at -70°C for RNA extraction.
The left lung was frozen in OCT compound (Miles, Elkhart, IN) for
immunohistochemical staining or minced in RPMI with 10% FBS for
eotaxin detection.
Chemokine detection by RNase protection assay
Total RNA was isolated using Trizol reagent. Probes for a panel
of chemokines were described by Xia et al. 23 . The assay was
performed as described by Xia et al. 24 . Briefly, RNA was dissolved
in 80% formamide, 0.4 M NaCl, 1 mM EDTA, and 40 mM
piperazine-N,N'-bis(2-ethanesulfonic acid),
heated to 85°C for 5 min, and hybridized for 10 h with
corresponding [-32P]UTP-labeled antisense probes at
55°C. The unhybridized RNA was digested with 50 U/ml RNase T1 (Life
Technologies) and 24 µg/ml RNase A (Sigma) for 1 h at 30°C.
After phenol-chloroform extraction and sodium acetate-ethanol
precipitation, the protected hybridized RNA was denatured and
electrophoresed on 10% polyacrylamide gel. The gel was dried and
exposed to film.
Eotaxin detection by ELISA
BAL collected from mice was spun, and supernatants were used to test BAL eotaxin levels. The left lobe of the lung were cut into small pieces in 0.5 ml of RPMI medium, incubated in 37°C for 30 min, and spun; the supernatants were used to test eotaxin levels in lung tissue. Eotaxin was detected by ELISA (R&D Systems).
Histology
Cytospins of BAL cells were fixed with methanol and stained with eosin and methylene blue (Fisher, Pittsburgh, PA). Leukocytes were analyzed by differential count of a total of 200–300 cells on coded slides. Lung was perfused, injected with OCT through the trachea, and frozen in OCT. Frozen lung sections were fixed with cold acetone (Fisher) and stained with 1 µg/ml of goat anti-mouse eotaxin Ab (R&D Systems) overnight. In the case of Ab blocking, 30 µg/ml recombinant eotaxin were added. The staining was followed by 1 µg/ml biotin-F(ab)2 horse anti-goat IgG (Jackson ImmunoResearch, West Grove, PA) and streptavidin-horseradish peroxidase (Jackson ImmunoResearch), and was visualized by 3-amino-9-ethylcarbazole (Sigma) substrate. Eosinophils were stained for cyanide-resistant eosinophil peroxidase activity as described by Li et al. 17 .
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our previous studies 17 , we found that adoptively transferred
Th1 and Th2 cells, stimulated in the lung, induced distinct patterns of
chemokines and inflammatory cell recruitment in lung parenchyma within
3 days. Thus, Th1 cells specifically expressed IFN- in the lung and
were potent inducers of interferon--inducible protein and neutrophil
recruitment. In contrast, Th2 cells expressing IL-4 and IL-5 (but not
IFN-) in the lung specifically induced eotaxin correlating with
eosinophil recruitment. Interestingly, a mix of Th1 and Th2 cells
showed a codominant expression of both Th1 and Th2 effects. Th1 and Th2
cells stimulated in vitro showed nearly identical patterns of chemokine
production (lymphotactin, MIP-1, MIP-1ß, and T cell activation
gene-3), suggesting that the differential effects on chemokine
expression and cell recruitment were mediated through lung parenchymal
cells. To determine the basis of these effects, we tested whether
specific cytokines produced by T cells could account for both the
induction of specific chemokine patterns and the apparent codominant
effects in inflammation.
To study the effects of Th1 or Th2 cytokines on chemokine production in
the lung, supernatants were generated from mature Th1 or Th2 cells by
stimulating these cells with ConA. The relative amounts of the various
cytokines in the supernatants were tested by ELISA (Table I
); among different batches of
supernatants, variation in individual cytokine concentrations was less
than two–threefold. These supernatants were given to naive BALB/c mice
intranasally, 50 µl/treatment and three treatments/day. Although we
cannot be certain what amounts of intranasally applied cytokines would
be equivalent to in vivo T cell production in the lung, we used this
frequent treatment over 2.5 days to reproduce the kinetics of
inflammation seen in our adoptive transfer studies 17 . After 2.5 days
of treatment, mice were sacrificed, and chemokine mRNAs were assayed
from lung tissue using an RNase protection assay. Equally high levels
of RANTES and KC mRNAs were detected in the lung tissues from Th1 or
Th2 supernatant-treated mice, compared with those in the control mice
(Fig. 1, A and B).
However, interferon--inducible protein was detectable only in Th1
supernatant-treated lungs, while higher expression of eotaxin and MCP-1
mRNAs was found in Th2 supernatant-treated lungs (Fig. 1, A
and B). These results suggested that some chemokines were
preferentially induced during Th1- or Th2-biased responses and
therefore may be responsible for the differences in patterns of
cellular infiltration during these responses.
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C), correlating with an increase in eotaxin expression
(Fig. 1, A and B). These results demonstrated
that Th2 cytokines, in relatively physiological proportions, were able
to induce a moderate lung eosinophilia, which probably was mediated by
the up-regulation of certain eosinophil chemoattractants, including
eotaxin. While the treatments with T cell supernatants were able to induce marked recruitment of inflammatory cells into BAL, histological observations revealed that the peribronchial and perivascular infiltrates were not as severe as those characteristic of T cell-mediated inflammation (not shown) 17 . This contrast illustrates the point that while cytokine effects can be revealed in the lung using intranasal administration, anatomic considerations may influence tissue pathology and animal physiology. Thus, activation of allergen specific T cells in the peribronchial spaces may cause highly localized induction of chemokine expression and subsequent preferential recruitment of eosinophils into peribronchial spaces. Activated eosinophils in these areas are likely to have more significant effects on airway hyperreactivity than those activated in alveolar spaces.
Individual Th2 cytokines induce different chemokine expression patterns
We next determined the relative contributions of various Th2
cytokines to the induction of eotaxin and eosinophilia. The major
cytokines produced by Th2 cells are IL-3, IL-4, IL-5, IL-10, and IL-13
(Table I). Since previous studies reported that IL-10 is an inhibitory
rather than a stimulatory cytokine on lung eosinophilia and asthma 25, 26 , we only tested the effects of IL-3, IL-4, IL-5, and IL-13 on
chemokine expression and cellular infiltration. As noted above, we
cannot be certain of the exact amounts and kinetics of T cell
production of cytokines in the lung, so we aimed to at least retain the
relative proportions of Th2 cytokines in these studies, based on the
ELISA analysis of Th2 supernatant preparations (Table I). In addition,
we again kept with a protocol limited to a 2.5-day stimulation to mimic
the previous studies on adoptively transferred T cells. Recombinant
cytokines were used, either individually or in combination, at
concentrations double those in the first batch of Th2 supernatant to
treat naive BALB/c mice. We found that these cytokines induced
different patterns of chemokine production (Fig. 2, A and
B). Compared with controls treated with culture medium
alone, IL-4 and IL-5 induced significantly higher levels of MIP-2 and
KC production; IL-4 also increased the production of MCP-1 (Fig. 2, A and B). Eotaxin was mainly induced by IL-13 and
to a lesser extent by IL-4 (Fig. 2, A–C). In
combination, these cytokines did not induce significantly higher
expression of any chemokine compared with that induced by individual
cytokines (Fig. 2, A–C), suggesting that there
is no synergy among these Th2 cytokines, at least for the induction of
chemokine expression. To rule out a role for host lymphocytes in any
secondary cytokine or chemokine induction, SCID mice were treated and
found to have the same response as normal BALB/c mice (Fig. 2C).
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D). Although IL-13 and IL-4 induced eotaxin expression,
these cytokines alone induced only a small increase in eosinophil
numbers in BAL (Fig. 2D), suggesting either that the levels
of chemokine expressed were not high enough, or other signals were
required to induce a significant lung eosinophilia. The latter
explanation seems more likely, as a combination of all four cytokines
produced a moderate infiltration of eosinophils (Fig. 2D).
Thus, while synergistic effects were not seen in the case of eotaxin
induction, some synergy among cytokines was evident with regard to
eosinophil recruitment. IL-13 is the major eotaxin-inducing cytokine produced by Th2 cells
Eotaxin has been shown to be a potent eosinophil chemoattractant,
so we focused further on the regulation of its production in the lung.
Among the Th2 cytokines tested, IL-13 was by far the most effective
cytokine inducing eotaxin in the lung, up-regulating both the eotaxin
mRNA expression and protein production (Fig. 2, A–C). Similar levels of eotaxin were detected in
the BAL of mice treated with a combination of four cytokines (IL-3,
IL-4, IL-5, and IL-13) as those in IL-13-treated mice,
suggesting that IL-13 was the major eotaxin-inducing factor without any
obvious synergistic effects among the cytokines tested (Fig. 2C).
In the lung, eotaxin was mainly produced by bronchial and alveolar
epithelial cells 27, 28 . Positive staining for eotaxin was detected
in these cells, especially the bronchial epithelial cells, of both
medium-treated (Fig. 3B) and
IL-13-treated (Fig. 3F) mice, but the intensity of staining
was much stronger in IL-13-treated lung. Low level eotaxin staining
could also be detected in lung tissue from untreated normal mice,
similar to the medium control (not shown). This result indicated that
eotaxin protein was constitutively produced in the lung as previously
reported 29, 30 , and the level was increased by IL-13 treatment. The
specificity of the staining was confirmed by the fact that adding an
excess amount of recombinant eotaxin to the detecting Ab (Fig. 3, C and G) blocked the positive staining.
Correlating with the increased eotaxin expression, IL-13 also caused a
low but definite peribronchial and perivascular infiltration of
eosinophils (Fig. 3, D and H), but the intensity
of infiltration was much lower compared with that in the lung with an
ongoing Th2 cell-mediated inflammation 17 .
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).
This result indicates that IL-13 is much more potent than IL-4 in the
induction of eotaxin in the lung.
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A). By contrast,
anti-IL-4 or anti-IL-5 Ab treatment of the Th2 supernatant did
not alter the level of eotaxin expression (not shown). In confirmation
of the effects on mRNA levels, eotaxin protein levels in both lung
tissue and BAL were also reduced when IL-13 was blocked in the
supernatant (Fig. 5B); in lung tissue, where higher
concentrations of eotaxin were detected, the levels of eotaxin protein
were also reduced close to the control levels (Fig. 5B).
This result again suggested that IL-13 is the major eotaxin-inducing
cytokine produced by Th2 cells. Correlating with the reduced eotaxin
expression in the BAL, a slight reduction (29%) in eosinophil
infiltration was noted in the BAL of mice given anti-IL-13-treated
Th2 supernatant (Fig. 5C). Although anti-IL-4 or
anti-IL-5 Abs did not inhibit eotaxin expression induced by Th2
supernatant, these Abs significantly reduced eosinophil infiltration in
BAL by 26 and 58%, respectively. This result suggests that while IL-4
and IL-5 may have important roles in the induction of lung
eosinophilia, they may act through mechanisms distinct from those
involving IL-13. This would help explain why the IL-4, IL-5, and IL-13
appear to have synergistic effects in eosinophil recruitment.
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synergizes with IL-13 for eotaxin induction in the lung
In lung epithelial cells and human fibroblasts, TNF-
substantially increased the level of eotaxin expression induced by
IFN- and IL-4, respectively, suggesting a synergistic effect between
TNF- and those cytokines 13, 14, 15 . Although Th2 cells produce very
low concentrations of TNF-, larger amounts of TNF- are likely to
be produced by macrophages, endothelial cells, and other cell types in
response to inflammatory stimuli. In addition, clinical studies have
shown that elevations of TNF- are readily detected in BAL from
patients with allergic lung inflammation 31, 32, 33, 34 . To study the
potential effect of TNF- on IL-13-induced eotaxin in lung tissue,
TNF- and IL-13 were used in combination to treat naive BALB/c mice.
Although TNF- by itself did not induce much eotaxin, it
significantly increased the eotaxin release induced by IL-13 at two
different concentrations (200 or 600 ng/ml IL-13 and TNF-) (Fig. 6). The cellular infiltration in BAL was
analyzed in mice given a low dose of cytokines (200 ng/ml). In
combination, these two cytokines also induced more eosinophil
infiltration, 7.6% of total BAL cells vs 0.6% in IL-13 alone and
0.3% in TNF- alone group (n = 4).
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IL-13 mediates biological functions on multiple cell types through
a receptor that shares a chain with IL-4 35 . The signaling pathway of
IL-13 is not always similar to that of IL-4, and different JAKs are
phosphorylated among different cell types treated with IL-13 36, 37, 38 .
To test whether JAK3 is important for IL-13 signal transduction in
airway epithelial cells, we treated JAK3-deficient mice 20 with IL-13
and measured eotaxin expression and eosinophil infiltration in the
lung. After 2 days of treatment, similar levels of eotaxin were
detected from the lung tissue of JAK-/- and
JAK3+/- littermate control mice (Fig. 7A), suggesting that JAK3 was
not required for IL-13-mediated eotaxin production by lung epithelial
cells. Curiously, however, eosinophilia was almost entirely absent in
the JAK3-/- mice (Fig. 7B), suggesting that
JAK3 is still critical in mediating signaling of another
IL-13-inducible component required for eosinophil recruitment in the
lung.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the presence of IL-1 or TNF- 13, 14 ,
and IL-4 also induces eotaxin production by human fibroblasts 15 . We
show in our present in vivo study that eotaxin produced by airway
epithelial cells is also strongly increased by IL-13.
IL-13 is produced by Th2 cells and shares many of its biological
functions with IL-4 in immune regulation. Accordingly, associations
between IL-13 and asthma have been suggested by various studies. IL-13
was produced by BAL cells of atopic asthma patients after allergen
challenge 43 , and increased IL-13 mRNA was detected in the bronchial
mucosa of asthma patients 44 . Furthermore, IL-13 could be detected in
BAL fluid or in the lung tissue in mouse asthma models induced either
by OVA priming or by Th2 cell adoptive transfer (our unpublished data).
Unlike IL-4, the production of IL-13 can be sustained through the late
asthmatic response, and the concentration of IL-13 secreted strongly
correlates with the number of eosinophils in BAL and in bronchial
submucosa 45 . Together, these results suggested that IL-13 might play
an important role in asthma pathogenesis. Our finding that IL-13
potently induced eotaxin production in the lung therefore provided one
mechanism of its action during asthma responses. Furthermore, the
synergistic effects between IL-13 and TNF- suggest a more potent
effect of IL-13 in up-regulating eotaxin expression during allergic
lung inflammation, under conditions where TNF- will be present
31, 32, 33, 34 .
IL-13 exhibits pleiotropic biological functions on multiple cell types, and it shares one chain of its receptor with IL-4. While JAK3 is one of the kinases transducing signals by the IL-4 receptor 46 , the signaling pathway of IL-13 seems to be quite variable, given that different JAKs are phosphorylated in different cell types treated with IL-13. For example, IL-13 induces JAK3 phosphorylation in primary human NK and T cells 36 , but phosphorylation was increased instead on Tyk2 in EBV-immortalized B cells treated by IL-13 37 , and in human colon carcinoma cell lines IL-13 induced phosphorylation and activation of JAK2 38 . In the present study, we tested the potential involvement of JAK3 in IL-13 signaling in airway epithelial cells. We found that IL-13 could induce eotaxin in the lung of JAK3-deficient mice at levels similar to those in the control mice, but it failed to induce eosinophil infiltration. This result suggested that JAK3 was not the kinase transducing IL-13 signals in airway epithelial cells, but this applied only to the induction of eotaxin expression. Since the recruitment of eosinophils involves multiple steps and factors, the lack of eosinophil infiltration in JAK3-/- mice could be due instead to a lack of adhesion molecule up-regulation, lack of eosinophil activation, or reduced eosinophil viability. It is known that IL-13 induces VCAM-1 expression on vascular endothelium 47 , and IL-13 may also act directly on eosinophils 48 . Either or both of these effects may depend on JAK3-mediated signaling.
Although eotaxin is very potent in local recruitment of eosinophils and
contributes largely to the development of lung eosinophilia 4 , its
up-regulation alone is not sufficient to induce severe eosinophilia in
the lung. Thus, neutralization of IL-13 and abrogation of eotaxin
induction still allowed for significant eosinophilia induced by IL-4
and IL-5. Eotaxin is constitutively expressed in a number of tissues,
including the lung and intestine. Constitutive expression of eotaxin in
intestine was required to maintain a baseline level of tissue
eosinophils, which may serve as a defense against parasite infection
49 . However, unlike the intestine, constitutive expression of eotaxin
in the lung was not sufficient to induce eosinophil infiltration into
the lung tissue, and even at an up-regulated level only a minor
eosinophilia was induced (Figs. 2 and 3H). This might be due
to a lack of certain additional signals in the lung required for large
numbers of eosinophil infiltration, including the possible direct role
of IL-4 and IL-5 in eosinophil recruitment and survival, and secondary
induction of additional chemokines. It is likely that the observed
synergy between Th2 cytokines is critical in efficient induction of
eosinophilia, since recombinant IL-13 alone was clearly not sufficient
to induce maximal eosinophil recruitment, even allowing for possible
secondary induction events during the 2.5-day treatment protocol.
Allergic asthma is often associated with Th2-biased responses and can be induced by adoptively transferred Th2 cells in animal models. It has been reported that the eotaxin-specific receptor CCR3 is expressed on Th2 cells, and eotaxin is chemotactic for Th2 cells in vitro 50, 51 . It is possible that besides recruiting eosinophils, eotaxin also induces local migration and activation of allergen-specific Th2 cells during asthma. The recruited Th2 cells could produce additional IL-13 and IL-4 to induce more eotaxin expression. Therefore, during allergic inflammatory responses, there may be a positive loop formed between Th2 cells and lung epithelial cells that amplifies the intensity of the inflammation. A break in this vicious cycle, especially in IL-13-mediated eotaxin expression, could help stop disease progression.
It has been reported that Th2 cytokines induce tissue eosinophilia through several different functions. Thus, IL-3 activates eosinophils and promotes their differentiation 52, 53 . IL-4 induces endothelial VCAM-1 expression, which together with ß1 integrin very late Ag-4 expression on eosinophils increases eosinophil adherence to the vessels 54, 55 . IL-5 induces differentiation and proliferation of bone marrow eosinophils, inducing blood eosinophilia, and activates or primes eosinophils and prolongs their survival in vitro 56, 57, 58, 59 . GM-CSF also stimulates the proliferation, differentiation, migration, activation, and survival of eosinophils in vitro 53, 60, 61 . Since all these cytokines can be produced by Th2 cells and were detected in BAL, they could show synergistic effects on the induction of lung eosinophilia. This is consistent with the observation in our study that none of the cytokines alone (GM-CSF also tested at 500 ng/ml, data not shown) was sufficient to induce a severe eosinophilia, but in combination they induced a moderate eosinophil infiltration in BAL. It has been reported that the expression of an IL-4 transgene in the lung 62 , or administration of microgram concentrations of IL-5, induced significant lung and BAL eosinophilia 63, 64 . While it suggests that higher concentrations of certain cytokines may overcome the requirement of other cytokines in inducing eosinophil infiltration, these cytokines may also induce secondary production of the additional cytokines necessary for eosinophil recruitment.
IL-13 is an important Th2 cytokine that regulates immune responses and affects functions of many immune effector cells 65 . In addition to other studies showing an association between IL-13 and asthma, our result provides a direct link between IL-13 and eotaxin production by airway epithelial cells, making it another potential target for asthma therapy. Additionally, the finding that knockout of JAK3-dependent mechanisms can prevent eosinophilia even in the face of eotaxin expression suggests additional directions for therapies.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David Lo, Department of Immunology IMM-25, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: MIP, macrophage-inflammatory protein; BAL, bronchoalveolar lavage; MCP, monocyte-chemotactic protein; JAK, Janus family kinase; TSRI, The Scripps Research Institute; rm, recombinant murine; GM-CSF, granulocyte-macrophage colony-stimulating factor.
Received for publication August 24, 1998. Accepted for publication November 24, 1998.
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W.-Q. Lai, H. H. Goh, Z. Bao, W. S. F. Wong, A. J. Melendez, and B. P. Leung The Role of Sphingosine Kinase in a Murine Model of Allergic Asthma J. Immunol., March 15, 2008; 180(6): 4323 - 4329. [Abstract] [Full Text] [PDF]
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M. Khodoun, C. Lewis, J.-Q. Yang, T. Orekov, C. Potter, T. Wynn, M. Mentink-Kane, G. K. Khurana Hershey, M. Wills-Karp, and F. D. Finkelman Differences in Expression, Affinity, and Function of Soluble (s)IL-4R{alpha} and sIL-13R{alpha}2 Suggest Opposite Effects on Allergic Responses J. Immunol., November 15, 2007; 179(10): 6429 - 6438. [Abstract] [Full Text] [PDF]
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Z. Bao, S. Lim, W. Liao, Y. Lin, C. Thiemermann, B. P. Leung, and W. S. F. Wong Glycogen Synthase Kinase-3beta Inhibition Attenuates Asthma in Mice Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 431 - 438. [Abstract] [Full Text] [PDF]
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S. R. Beaty, C. E. Rose Jr., and S.-s. J. Sung Diverse and Potent Chemokine Production by Lung CD11bhigh Dendritic Cells in Homeostasis and in Allergic Lung Inflammation J. Immunol., February 1, 2007; 178(3): 1882 - 1895. [Abstract] [Full Text] [PDF]
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D. C. Webb, Y. Cai, K. I. Matthaei, and P. S. Foster Comparative Roles of IL-4, IL-13, and IL-4R{alpha} in Dendritic Cell Maturation and CD4+ Th2 Cell Function J. Immunol., January 1, 2007; 178(1): 219 - 227. [Abstract] [Full Text] [PDF]
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I. Meyts, P. W. Hellings, G. Hens, B. M. Vanaudenaerde, B. Verbinnen, H. Heremans, P. Matthys, D. M. Bullens, L. Overbergh, C. Mathieu, et al. IL-12 Contributes to Allergen-Induced Airway Inflammation in Experimental Asthma J. Immunol., November 1, 2006; 177(9): 6460 - 6470. [Abstract] [Full Text] [PDF]
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W. M. Gwinn, J. M. Damsker, R. Falahati, I. Okwumabua, A. Kelly-Welch, A. D. Keegan, C. Vanpouille, J. J. Lee, L. A. Dent, D. Leitenberg, et al. Novel Approach to Inhibit Asthma-Mediated Lung Inflammation Using Anti-CD147 Intervention J. Immunol., October 1, 2006; 177(7): 4870 - 4879. [Abstract] [Full Text] [PDF]
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Y. Sun, S. E. Blink, W. Liu, Y. Lee, B. Chen, J. Solway, J. Weinstock, L. Chen, and Y.-X. Fu Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation J. Immunol., July 15, 2006; 177(2): 814 - 821. [Abstract] [Full Text] [PDF]
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V. Hernandez-Hansen, J. D. J. Bard, C. A. Tarleton, J. A. Wilder, C. A. Lowell, B. S. Wilson, and J. M. Oliver Increased Expression of Genes Linked to Fc{epsilon}RI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells J. Immunol., December 15, 2005; 175(12): 7880 - 7888. [Abstract] [Full Text] [PDF]
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D. A. Kuperman, X. Huang, L. Nguyenvu, C. Holscher, F. Brombacher, and D. J. Erle IL-4 Receptor Signaling in Clara Cells Is Required for Allergen-Induced Mucus Production J. Immunol., September 15, 2005; 175(6): 3746 - 3752. [Abstract] [Full Text] [PDF]
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K. B. Moerloose, R. A. Pauwels, and G. F. Joos Short-Term Cigarette Smoke Exposure Enhances Allergic Airway Inflammation in Mice Am. J. Respir. Crit. Care Med., July 15, 2005; 172(2): 168 - 172. [Abstract] [Full Text] [PDF]
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W. Duan, J. H. P. Chan, K. McKay, J. R. Crosby, H. H. Choo, B. P. Leung, J. G. Karras, and W. S. F. Wong Inhaled p38{alpha} Mitogen-activated Protein Kinase Antisense Oligonucleotide Attenuates Asthma in Mice Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 571 - 578. [Abstract] [Full Text] [PDF]
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M. S. Thomas, S. L. Kunkel, and N. W. Lukacs Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9 J. Immunol., July 1, 2004; 173(1): 615 - 623. [Abstract] [Full Text] [PDF]
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T. Kikuchi, J. D. Shively, J. S. Foley, J. M. Drazen, and D. J. Tschumperlin Differentiation-dependent responsiveness of bronchial epithelial cells to IL-4/13 stimulation Am J Physiol Lung Cell Mol Physiol, July 1, 2004; 287(1): L119 - L126. [Abstract] [Full Text] [PDF]
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W. Duan, J. H. P. Chan, C. H. Wong, B. P. Leung, and W. S. F. Wong Anti-Inflammatory Effects of Mitogen-Activated Protein Kinase Kinase Inhibitor U0126 in an Asthma Mouse Model J. Immunol., June 1, 2004; 172(11): 7053 - 7059. [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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K. Raman, M. H. Kaplan, C. M. Hogaboam, A. Berlin, and N. W. Lukacs STAT4 Signal Pathways Regulate Inflammation and Airway Physiology Changes in Allergic Airway Inflammation Locally Via Alteration of Chemokines J. Immunol., April 1, 2003; 170(7): 3859 - 3865. [Abstract] [Full Text] [PDF]
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T. R. Johnson, R. A. Parker, J. E. Johnson, and B. S. Graham IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge J. Immunol., February 15, 2003; 170(4): 2037 - 2045. [Abstract] [Full Text] [PDF]
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K. Y. Larbi, J. P. Dangerfield, F. J. Culley, D. Marshall, D. O. Haskard, P. J. Jose, T. J. Williams, and S. Nourshargh P-selectin mediates IL-13-induced eosinophil transmigration but not eotaxin generation in vivo: a comparative study with IL-4-elicited responses J. Leukoc. Biol., January 1, 2003; 73(1): 65 - 73. [Abstract] [Full Text] [PDF]
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A. Kibe, H. Inoue, S. Fukuyama, K. Machida, K. Matsumoto, H. Koto, T. Ikegami, H. Aizawa, and N. Hara Differential Regulation by Glucocorticoid of Interleukin-13-induced Eosinophilia, Hyperresponsiveness, and Goblet Cell Hyperplasia in Mouse Airways Am. J. Respir. Crit. Care Med., January 1, 2003; 167(1): 50 - 56. [Abstract] [Full Text] [PDF]
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M. S. Thomas, S. L. Kunkel, and N. W. Lukacs Differential Role of IFN-{gamma}-Inducible Protein 10 kDa in a Cockroach Antigen-Induced Model of Allergic Airway Hyperreactivity: Systemic Versus Local Effects J. Immunol., December 15, 2002; 169(12): 7045 - 7053. [Abstract] [Full Text] [PDF]
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C. Taube, C. Duez, Z.-H. Cui, K. Takeda, Y.-H. Rha, J.-W. Park, A. Balhorn, D. D. Donaldson, A. Dakhama, and E. W. Gelfand The Role of IL-13 in Established Allergic Airway Disease J. Immunol., December 1, 2002; 169(11): 6482 - 6489. [Abstract] [Full Text] [PDF]
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J. M. Matheson, R. Lemus, R. W. Lange, M. H. Karol, and M. I. Luster Role of Tumor Necrosis Factor in Toluene Diisocyanate Asthma Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 396 - 405. [Abstract] [Full Text] [PDF]
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S. A. Ritz, M. J. Cundall, B. U. Gajewska, D. Alvarez, J.-C. Gutierrez-Ramos, A. J. Coyle, A. N. J. McKenzie, M. R. Stampfli, and M. Jordana Granulocyte Macrophage Colony-Stimulating Factor-Driven Respiratory Mucosal Sensitization Induces Th2 Differentiation and Function Independently of Interleukin-4 Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 428 - 435. [Abstract] [Full Text] [PDF]
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N. Hizawa, E. Yamaguchi, S. Konno, Y. Tanino, E. Jinushi, and M. Nishimura A Functional Polymorphism in the RANTES Gene Promoter Is Associated with the Development of Late-Onset Asthma Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 686 - 690. [Abstract] [Full Text] [PDF]
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H. Harlin, E. Podack, M. Boothby, and M.-L. Alegre TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism J. Immunol., September 1, 2002; 169(5): 2451 - 2459. [Abstract] [Full Text] [PDF]
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S. D. Hurst, T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, et al. New IL-17 Family Members Promote Th1 or Th2 Responses in the Lung: In Vivo Function of the Novel Cytokine IL-25 J. Immunol., July 1, 2002; 169(1): 443 - 453. [Abstract] [Full Text] [PDF]
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J. M. Schuh, K. Blease, S. L. Kunkel, and C. M. Hogaboam Eotaxin/CCL11 is involved in acute, but not chronic, allergic airway responses to Aspergillus fumigatus Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L198 - L204. [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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M. T. Borchers, P. J. Justice, T. Ansay, V. Mancino, M. P. McGarry, J. Crosby, M. I. Simon, N. A. Lee, and J. J. Lee Gq Signaling Is Required for Allergen-Induced Pulmonary Eosinophilia J. Immunol., April 1, 2002; 168(7): 3543 - 3549. [Abstract] [Full Text] [PDF]
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J. E. Durbin, T. R. Johnson, R. K. Durbin, S. E. Mertz, R. A. Morotti, R. S. Peebles, and B. S. Graham The Role of IFN in Respiratory Syncytial Virus Pathogenesis J. Immunol., March 15, 2002; 168(6): 2944 - 2952. [Abstract] [Full Text] [PDF]
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M. O. Daines and G. K. K. Hershey A Novel Mechanism by Which Interferon-gamma Can Regulate Interleukin (IL)-13 Responses. EVIDENCE FOR INTRACELLULAR STORES OF IL-13 RECEPTOR alpha -2 AND THEIR RAPID MOBILIZATION BY INTERFERON-gamma J. Biol. Chem., March 15, 2002; 277(12): 10387 - 10393. [Abstract] [Full Text] [PDF]
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E. F. Foxman, M. Zhang, S. D. Hurst, T. Muchamuel, D. Shen, E. F. Wawrousek, C.-C. Chan, and I. Gery Inflammatory Mediators in Uveitis: Differential Induction of Cytokines and Chemokines in Th1- Versus Th2-Mediated Ocular Inflammation J. Immunol., March 1, 2002; 168(5): 2483 - 2492. [Abstract] [Full Text] [PDF]
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L. A. Jopling, I. Sabroe, D. P. Andrew, T. J. Mitchell, Y. Li, M. R. Hodge, T. J. Williams, and J. E. Pease The Identification, Characterization, and Distribution of Guinea Pig CCR4 and Epitope Mapping of a Blocking Antibody J. Biol. Chem., February 22, 2002; 277(9): 6864 - 6873. [Abstract] [Full Text] [PDF]
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S. J. McMillan, B. Bishop, M. J. Townsend, A. N. McKenzie, and C. M. Lloyd The Absence of Interleukin 9 Does Not Affect the Development of Allergen-induced Pulmonary Inflammation nor Airway Hyperreactivity J. Exp. Med., January 7, 2002; 195(1): 51 - 57. [Abstract] [Full Text] [PDF]
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C. Albanesi, C. Scarponi, S. Sebastiani, A. Cavani, M. Federici, S. Sozzani, and G. Girolomoni A cytokine-to-chemokine axis between T lymphocytes and keratinocytes can favor Th1 cell accumulation in chronic inflammatory skin diseases J. Leukoc. Biol., October 1, 2001; 70(4): 617 - 623. [Abstract] [Full Text] [PDF]
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A. G. Jarnicki, T. Tsuji, and W. R. Thomas Inhibition of mucosal and systemic Th2-type immune responses by intranasal peptides containing a dominant T cell epitope of the allergen Der p 1 Int. Immunol., October 1, 2001; 13(10): 1223 - 1231. [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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O. T. M. Chan, V. Paliwal, J. M. McNiff, S.-H. Park, A. Bendelac, and M. J. Shlomchik Deficiency in {beta}2-Microglobulin, But Not CD1, Accelerates Spontaneous Lupus Skin Disease While Inhibiting Nephritis in MRL-Faslpr Mice: An Example of Disease Regulation at the Organ Level J. Immunol., September 1, 2001; 167(5): 2985 - 2990. [Abstract] [Full Text] [PDF]
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A. G. Tesciuba, S. Subudhi, R. P. Rother, S. J. Faas, A. M. Frantz, D. Elliot, J. Weinstock, L. A. Matis, J. A. Bluestone, and A. I. Sperling Inducible Costimulator Regulates Th2-Mediated Inflammation, but Not Th2 Differentiation, in a Model of Allergic Airway Disease J. Immunol., August 15, 2001; 167(4): 1996 - 2003. [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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N. W. Lukacs, K. K. Tekkanat, A. Berlin, C. M. Hogaboam, A. Miller, H. Evanoff, P. Lincoln, and H. Maassab Respiratory Syncytial Virus Predisposes Mice to Augmented Allergic Airway Responses Via IL-13-Mediated Mechanisms J. Immunol., July 15, 2001; 167(2): 1060 - 1065. [Abstract] [Full Text] [PDF]
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M. J. Dobrzanski, J. B. Reome, and R. W. Dutton Role of Effector Cell-Derived IL-4, IL-5, and Perforin in Early and Late Stages of Type 2 CD8 Effector Cell-Mediated Tumor Rejection J. Immunol., July 1, 2001; 167(1): 424 - 434. [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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M. Stassen, C. Muller, M. Arnold, L. Hultner, S. Klein-Hessling, C. Neudorfl, T. Reineke, E. Serfling, and E. Schmitt IL-9 and IL-13 Production by Activated Mast Cells Is Strongly Enhanced in the Presence of Lipopolysaccharide: NF-{{kappa}}B Is Decisively Involved in the Expression of IL-9 J. Immunol., April 1, 2001; 166(7): 4391 - 4398. [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. Kawasaki, H. Takizawa, H. Yoneyama, T. Nakayama, R. Fujisawa, M. Izumizaki, T. Imai, O. Yoshie, I. Homma, K. Yamamoto, et al. Intervention of Thymus and Activation-Regulated Chemokine Attenuates the Development of Allergic Airway Inflammation and Hyperresponsiveness in Mice J. Immunol., February 1, 2001; 166(3): 2055 - 2062. [Abstract] [Full Text] [PDF]
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 F. H. Falcone, H. Haas, and B. F. Gibbs The human basophil: a new appreciation of its role in immune responses Blood, December 15, 2000; 96(13): 4028 - 4038. [Full Text] [PDF]
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N. Zimmermann, S. P. Hogan, A. Mishra, E. B. Brandt, T. R. Bodette, S. M. Pope, F. D. Finkelman, and M. E. Rothenberg Murine Eotaxin-2: A Constitutive Eosinophil Chemokine Induced by Allergen Challenge and IL-4 Overexpression J. Immunol., November 15, 2000; 165(10): 5839 - 5846. [Abstract] [Full Text] [PDF]
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R. Umeshita-Suyama, R. Sugimoto, M. Akaiwa, K. Arima, B. Yu, M. Wada, M. Kuwano, K. Nakajima, N. Hamasaki, and K. Izuhara Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor {alpha} chain 1: redundancy of requirement of tyrosine residue for STAT3 activation Int. Immunol., November 1, 2000; 12(11): 1499 - 1509. [Abstract] [Full Text] [PDF]
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J. Deng, V. P. Yeung, D. Tsitoura, R. H. DeKruyff, D. T. Umetsu, and S. Levy Allergen-Induced Airway Hyperreactivity Is Diminished in CD81-Deficient Mice J. Immunol., November 1, 2000; 165(9): 5054 - 5061. [Abstract] [Full Text] [PDF]
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M. Throsby, A. Herbelin, J.-M. Pleau, and M. Dardenne CD11c+ Eosinophils in the Murine Thymus: Developmental Regulation and Recruitment upon MHC Class I-Restricted Thymocyte Deletion J. Immunol., August 15, 2000; 165(4): 1965 - 1975. [Abstract] [Full Text] [PDF]
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S. M. Propst, R. Denson, E. Rothstein, K. Estell, and L. M. Schwiebert Proinflammatory and Th2-Derived Cytokines Modulate CD40-Mediated Expression of Inflammatory Mediators in Airway Epithelia: Implications for the Role of Epithelial CD40 in Airway Inflammation J. Immunol., August 15, 2000; 165(4): 2214 - 2221. [Abstract] [Full Text] [PDF]
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B. LAMKHIOUED, E. A. GARCIA-ZEPEDA, S. ABI-YOUNES, H. NAKAMURA, S. JEDRZKIEWICZ, L. WAGNER, P. M. RENZI, Z. ALLAKHVERDI, C. LILLY, Q. HAMID, et al. Monocyte Chemoattractant Protein (MCP)-4 Expression in the Airways of Patients with Asthma . Induction in Epithelial Cells and Mononuclear Cells by Proinflammatory Cytokines Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 723 - 732. [Abstract] [Full Text] [PDF]
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M. Zaitsu, Y. Hamasaki, M. Matsuo, A. Kukita, K. Tsuji, M. Miyazaki, R. Hayasaki, E. Muro, S. Yamamoto, I. Kobayashi, et al. New induction of leukotriene A4 hydrolase by interleukin-4 and interleukin-13 in human polymorphonuclear leukocytes Blood, July 15, 2000; 96(2): 601 - 609. [Abstract] [Full Text] [PDF]
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D. C. Webb, A. N. J. McKenzie, A. M. L. Koskinen, M. Yang, J. Mattes, and P. S. Foster Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity J. Immunol., July 1, 2000; 165(1): 108 - 113. [Abstract] [Full Text] [PDF]
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M. J. Dobrzanski, J. B. Reome, and R. W. Dutton Type 1 and Type 2 CD8+ Effector T Cell Subpopulations Promote Long-Term Tumor Immunity and Protection to Progressively Growing Tumor J. Immunol., January 15, 2000; 164(2): 916 - 925. [Abstract] [Full Text] [PDF]
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C. Bandeira-Melo, M. F. Serra, B. L. Diaz, R. S. B. Cordeiro, P. M. R. Silva, H. L. Lenzi, Y. S. Bakhle, C. N. Serhan, and M. A. Martins Cyclooxygenase-2-Derived Prostaglandin E2 and Lipoxin A4 Accelerate Resolution of Allergic Edema in Angiostrongylus costaricensis-Infected Rats: Relationship with Concurrent Eosinophilia J. Immunol., January 15, 2000; 164(2): 1029 - 1036. [Abstract] [Full Text] [PDF]
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S. Ying, Q. Meng, K. Zeibecoglou, D. S. Robinson, A. Macfarlane, M. Humbert, and A. B. Kay Eosinophil Chemotactic Chemokines (Eotaxin, Eotaxin-2, RANTES, Monocyte Chemoattractant Protein-3 (MCP-3), and MCP-4), and C-C Chemokine Receptor 3 Expression in Bronchial Biopsies from Atopic and Nonatopic (Intrinsic) Asthmatics J. Immunol., December 1, 1999; 163(11): 6321 - 6329. [Abstract] [Full Text] [PDF]
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C. Stellato, S. Matsukura, A. Fal, J. White, L. A. Beck, D. Proud, and R. P. Schleimer Differential Regulation of Epithelial-Derived C-C Chemokine Expression by IL-4 and the Glucocorticoid Budesonide J. Immunol., November 15, 1999; 163(10): 5624 - 5632. [Abstract] [Full Text] [PDF]
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I. Sabroe, M. J. Peck, B. J. Van Keulen, A. Jorritsma, G. Simmons, P. R. Clapham, T. J. Williams, and J. E. Pease A Small Molecule Antagonist of Chemokine Receptors CCR1 and CCR3. POTENT INHIBITION OF EOSINOPHIL FUNCTION AND CCR3-MEDIATED HIV-1 ENTRY J. Biol. Chem., August 18, 2000; 275(34): 25985 - 25992. [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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