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, But Not on Eosinophils1
,§
*
Sections of Pulmonary and Critical Care Medicine and
Immunobiology and
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520;
§
Pathology and Laboratory Medicine Service, Veterans Administration Connecticut Health Care System, West Haven, CT 06516;
¶
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; and
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Department of Immunology, University of Cape Town, Cape Town, South Africa
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice, mucus is not induced, and BAL
eosinophilia is absent. These data suggest that in the absence of IL-4,
IL-13 may be critical for Th2-induced mucus production and
eosinophilia. To determine whether eosinophils are important in mucus
production, IL-5-/- Th2 cells were transferred into
IL-5-/- recipients. Eosinophilia was abolished, yet mucus
staining in the epithelium persisted. These studies show definitively
that IL-5, eosinophils, or mast cells are not essential, but signaling
through IL-4R is critically important in Th2 cell stimulation of
mucus production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In asthma, mucus hypersecretion is associated with inflammation. A variety of inflammatory mediators have been shown to stimulate mucus secretion, including histamine, PGs, leukotrienes, platelet-activating factor, and eosinophil cationic (3, 4). More recently, the cytokines IL-4, IL-5, and IL-9 have been shown to influence mucus secretion (5, 6, 7). Despite multiple potential mechanisms, the precise inflammatory pathways that stimulate increased mucus production are not well defined.
Animal models of asthma have helped to define the critical importance of CD4 T cells and their cytokines in the development of airway inflammation and eosinophilia. In a mouse model we recently defined a system of CD4 Th2 cell-induced allergic airway inflammation (8, 9). We showed that stimulation of airway epithelial mucus production and airway hyperresponsiveness are dependent on local inflammation by Th2, but not Th1, cells. Despite previously described associations with IL-4, we showed that both mucus production and airway hyperresponsiveness could be stimulated in the absence of IL-4.
IL-4R and IL-13R share a common receptor chain, IL-4R, and common
signal transduction mechanism through Stat6. In mice lacking in
IL-4R or Stat6, many functions of IL-4 and IL-13 are inhibited,
including Th2 cell differentiation, IgE production, and reduction in
airway epithelial mucus (10, 11, 12, 13, 14, 15, 16). However, in these models Th2 cell
development was impaired, and Th2 effector function in mucus production
could not be determined.
In the current studies we dissect further the mechanisms of CD4 Th2-induced mucus production using Th2 cells generated in vitro from cytokine gene-deficient mice. After transfer into wild-type and cytokine receptor-deficient mice we assess the effector function of Th2 cells on airway mucus induction. We identify the critical importance of IL-4R/IL-13R signaling in Th2 cell stimulation of mucus production. Furthermore, we show definitively that IL-5, eosinophils, and mast cells are not essential for the induction of mucus production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD4 T cell donors were DO11.10 mice (BALB/c), which are
transgenic for the TCR recognizing OVA peptide 323–339
(pOVA323–339;3 provided by K. Murphy, Washington University, St. Louis, MO) (17),
DO11.10 IL-4-/- mice (bred in our facilities),
and IL-5-/- (C57BL/6; provided by M. Kopf,
Basel Institute for Immunology, Basel, Switzerland) (18). Transfer
recipients were 6–12 wk of age and included BALB/c, C57BL/6, W/Wv
((WB/Rej-kitW/+ x
C57BL6J-kitW-v/+)F1), and their wild type
littermates, WBB6F1 (all from The Jackson Laboratory, Bar
Harbor, ME), and IL-4R-/- mice
(BALB/c).4
Generation of Th1 or Th2 cells
To generate Th2 cells from nontransgenic mice, C57BL/6 or
IL-5-/- mice were injected i.p. with 100 µg
of OVA (Sigma, St. Louis, MO) in 4.5 mg of alum (Immuject, Sigma). Five
days after immunization, spleens and local draining lymph nodes were
harvested, and CD4 T cells were isolated by negative selection as
previously described (19), using mAbs to CD8 (clone 53-6.72 and clone
2.43) (20), class II MHC I-Ad (212.A1) (21), and
anti-Ig-coated magnetic beads (Collaborative Research, Bedford,
MA). To generate DO11.10 or DO11.10 IL-4-/- Th2
cells, CD4 T cells were isolated from spleens. Syngeneic T-depleted
splenocytes were used as APC in all cultures and were prepared by
negative selection using Abs to CD4 (GK1.5) (22), anti-CD8 and
anti-Thy-1 (23), and treatment with rabbit complement. APCs were
treated with mitomycin C. All cultures were set up in flasks containing
equal numbers of CD4 T cells and APCs at a concentration of 0.5–3
x 106 cells/ml and OVA at 100 µg/ml for nontransgenic
CD4 T cells or pOVA323–339 at 5 µg/ml for DO11.10 cells,
IL-4 at 200 U/ml (Collaborative Research), and anti-IFN-
(XMG1.2) (24) at an inhibitory concentration. Cultures were maintained
for 4 days.
Transfer of cells and aerosol administration of OVA
Cultured Th2-like cells were harvested after 4 days and washed with PBS, and 5 x 106 cells were injected i.v. into syngeneic recipients. WBB6F1 and W/Wv mice received C57BL/6-derived Th2 cells. One day after transfer of cells, mice were challenged with inhaled 1% OVA/0.01% Tween-20 in PBS for 20 min daily for 7 days using an ultrasonic nebulizer (1- to 5-µm particles by manufacturer’s specifications, UltraAir NE-U07, OMRON, Vernon Hills, IL) as previously described (8).
Bronchoalveolar lavag (BAL)
BAL was performed by cannulation of the trachea and lavage with 1 ml of PBS. Cytospin preparations of BAL cells were stained with Diff-Quik (Baxter Healthcare, Miami, FL), and differentials were performed on 200 cells based on morphology and staining characteristics.
Cytokine assays
At the time of transfer, an aliquot of Th2-like cells was
retained for restimulation. CD4 T cells (1 x 106/ml)
and 1 x 106/ml freshly isolated APCs were cultured
with OVA (100 µg/ml) or pOVA (5 µg/ml). Supernatants were collected
at 48 h. Cell supernatants were analyzed by ELISA for IFN-,
IL-4, IL-5, (Endogen, Cambridge, MA), and IL-13 (R&D Systems,
Minneapolis, MN). The lower limit of sensitivity for the ELISAs were
0.6 ng/ml (IFN-), 5 pg/ml (IL-4), 0.010 ng/ml (IL-5), and 8 pg/ml
(IL-13).
FACS analysis
At the time of transfer, FACS (Becton Dickinson, Mountain View, CA) analysis was performed on Th2 cell preparations to determine the purity of transferred cell populations. Cells were stained with anti-CD4 (Quantum Red-L3T4, Sigma) and, in mice that received DO11.10 transgenic CD4 cells, with the biotinylated anticlonotypic Ab, KJ1-26 (25), and FITC-avidin D (Vector, Burlingame, CA). KJ1-26 is specific for the transgenic TCR in the DO11.10 mice. Transferred cells were uniformly >96% CD4 positive. After a period of inhalational exposure, BAL cells were also analyzed by FACS using these Abs.
Lung histology
Lungs were prepared for histology by perfusing the animal via the right ventricle with 20 ml of PBS. Lungs were then inflated with 1.0 ml of fixative instilled through a tracheostomy tube. Samples for paraffin sectioning were formalin fixed and sectioned in the coronal plane at 5 µm ensuring that central airways were visible. Sections were stained with hematoxylin and eosin and periodic acid-Schiff (PAS). The histological mucus index (HMI) was determined on PAS-stained sections on which marker dots in a grid with 2-mm spacing were placed over the entire lung section. The slide was examined at x100 final magnification with a rectangular 10-mm square reticule grid (American Optical, Buffalo, NY) inserted into one eyepiece. Each marker dot was placed in the lower left corner of the field, and all intersections of airway epithelium with the reticule grid were counted in that field, distinguishing mucus-containing or normal epithelium. Approximately 25% of the total lung section was scored. The ratio of total number of mucus-positive intersections and the total of all intersections, which we call the HMI, is equivalent to the linear percentage of epithelium positive for mucus (26). This index was calculated for each mouse lung and then the mean HMI was calculated for each experimental group.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously showed that when Th1 or Th2 cells were generated in
vitro from TCR transgenic DO11.10 mice and transferred into recipient
mice, and mice were exposed to inhaled OVA, only the mice that received
DO11.10 Th2 cells exhibited eosinophilic airway inflammation and
increased mucus staining in the bronchial epithelium (8). Mice that
received Th1 cells showed inflammation without eosinophilia or mucus
production. Thus, activated Th2 cells stimulated inflammation leading
to mucus hyperproduction. In mice that received DO11.10
IL-4+/+ or IL-4-/- Th2
cells, mucus was induced at similar levels (Fig. 1
A). These data confirmed our
previous findings and showed that in a TCR transgenic system Th2 cell
production of IL-4 is not necessary for mucus induction (8). Mucus
production was completely IL-4 independent, since transfer of
IL-4-/- Th2 cells into IL-4-deficient mice
still led to the induction of mucus (data not shown). In mice that
received IL-4-/- Th2 cells, although there was
a reduction in airway eosinophilia (Fig. 1B), it was still
possible that small numbers of eosinophils could stimulate mucus
production.
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To investigate further which factors secreted by Th2 cells
stimulate increased mucus production, we asked whether IL-13 might
substitute for IL-4 in mucus production. Since IL-13 and IL-4 have many
overlapping functions due to the use of a common receptor chain,
IL-4R, it was possible that in the absence of IL-4, IL-13 could
stimulate mucus production. To test whether signaling via the
IL-4R/IL-13R mediates mucus production by Th2 cells, we generated
DO11.10 IL-4-/- Th2 cells in vitro and
transferred the cells into BALB/c (IL-4R+/+)
and IL-4R-/- mice. At the time of transfer,
IL-4-/- Th2 cells produced high levels of IL-13
and IL-5 and minimal IFN-, but only
IL-4R+/+-recipient mice and not
IL-4R-/- mice could respond to IL-13 (Fig. 2A). Mice were exposed to
inhaled OVA and then assessed for inflammatory changes in the lungs. In
IL-4R-/- mice that received
IL-4-/- Th2 cells and inhaled OVA, mucus
staining was absent, while IL-4R+/+-recipient
mice exhibited extensive mucus staining in the bronchial epithelium
(Fig. 2B and Fig. 3). Airway
inflammation, as shown by the number of BAL cells recovered, was
modestly reduced in IL-4R-/--recipient mice
compared with that in IL-4R+/+ mice (Fig. 2C). There was no airway eosinophilia in the
IL-4R-/- mice, while 20% of the BAL cells
were eosinophils in IL-4R+/+ mice after
transfer of IL-4-/- Th2 cells. CD4 expressing
transgenic cells (KJ1.26+) were found in similar numbers in
wild-type and IL-4R-/- mice (Fig. 2C), indicating that the failure to observe mucus production
and eosinophilia is not due to the absence of transgenic Th2 cells in
the lung. These data show that in the absence of IL-4, IL-4R
controls Th2-induced mucus production and airway eosinophilia,
indicating a possible role for IL-13 in stimulating these processes.
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Since the induction of airway eosinophilia and mucus were both
blocked in IL-4R-/- mice, it was still
unclear whether eosinophils were required for mucus induction by Th2
cells. IL-5 is essential for augmenting eosinophil recruitment to sites
of inflammation (18). To determine the importance of lung eosinophils
in mucus production, we generated OVA-specific
IL-5-/- Th2 cells in vitro and transferred them
into C57BL/6 (IL-5+/+)-recipient mice. At the
time of transfer, IL-5+/+ Th2 cells and IL-5
-/- Th2 cells both produced high levels of IL-4
and IL-13, but only IL-5+/+ Th2 cells produced
IL-5 (Fig. 4A). Mice that
received IL-5-/- Th2 cells exhibited decreased
BAL eosinophilia compared with mice that received
IL-5+/+ Th2 cells, yet airway epithelial mucus
staining was similar in the two groups (Fig. 4, B andC). C57BL/6 (IL-5+/+) and
IL-5-/- mice that did not receive cells and
were exposed to inhaled OVA alone exhibited mucus staining in <5% of
airway epithelial cells, and eosinophils were not present in the BAL
(data not shown). Although these experiments suggested that mucus
staining did not correlate with airway eosinophilia, it was still
possible that epithelial stimulation required only a small number of
activated eosinophils to induce a threshold level of mucus. To
completely eliminate IL-5 from this system, we transferred
IL-5-/- Th2 cells into
IL-5-/--recipient mice. BAL eosinophilia was
abolished when IL-5 is absent from both the transferred cells and
recipient mice, yet mucus staining was induced at similar levels in
mice that received IL-5+/+ or
IL-5-/- Th2 cells. These studies show that Th2
cells can stimulate airway epithelial mucus production in the absence
of IL-5 and airway eosinophilia.
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Mast cells do not contribute to Th2-induced mucus production
Mast cells, upon activation, synthesize and secrete the cytokines
IL-4 and IL-13 and mucus secretagogues such as histamine and
leukotrienes (4, 27, 28). IL-4R/IL-13R are present on mast cells and
are believed to be important for activation, and IL-4/IL-13 are
critical for the production of IgE Abs (13, 29, 30, 31). To determine
whether mucus production stimulated by Th2 cells was mediated through
activation of mast cells, we generated OVA-specific Th2 cells and
transferred them into wild-type and mast cell-deficient
(W/Wv) mice. After exposure to inhaled OVA, both mast
cell-deficient and wild-type mice exhibited equivalent mucus staining
in the bronchial epithelium (Fig. 5).
Wild-type and W/Wv mice that were only exposed to inhaled
OVA exhibited mucus staining in <5% of airway epithelial cells (data
not shown). Thus, these experiments show that increased mucus
production induced by Th2 cells is independent of mast cell activation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cytokines secreted by Th2 cells determine their effector function
in an inflammatory response. We studied the roles of IL-4, IL-5, and
IL-13 to determine how Th2 cell activation resulted in the induction of
mucus production. We generated Th2 cells from mice deficient in IL-4
and IL-5 and observed the effects in recipient animals after
inhalational challenge. Although IL-4 is critical for the generation of
Th2 cells, we previously determined that it was not required for the
induction of airway epithelial mucus production (8). We now show that
in the absence of IL-4, IL-4R signaling is required to stimulate
mucus production. The lack of mucus staining in
IL-4R-/- mice was not due to the absence of
eosinophils, since mucus can be induced by Th2 cells in the absence of
IL-5 and eosinophils. In these studies we have blocked the effects of
individual Th2 cytokines to dissect the inflammatory pathways of IL-4,
IL-5, and IL-13 in the induction of airway epithelial mucus production.
The cytokine microenvironment in which a naive CD4 T cell is stimulated
determines whether it will differentiate into a Th1 cell, secreting
IFN-, or a Th2 cell, secreting IL-4, IL-5, and IL-13. If stimulated
in the presence of IL-4, a population of CD4 T cells will become Th2
cells, while in the absence of IL-4 and/or IL-13, they will
differentiate into Th1 cells (13, 15, 30, 31). Previous studies in
Stat6-deficient mice, which have defective signaling through both IL-4R
and IL-13R, showed that when these mice were primed with Ag,
predominantly IFN--secreting Th1 cells were generated (10, 11, 12). When
primed Stat6-/- mice were challenged with
inhaled Ag (14), it was difficult to determine whether the inhibition
of mucus production that was observed reflected a blockade of
IL-4/IL-13 or the presence of activated Th1 cells in the lungs.
Inflammation induced by mixed populations of Th1 and Th2 cells leads to
a dominance of Th1 effects and reduced mucus production, as shown when
we transferred both Th1 and Th2 cells together into recipient mice and
challenged mice with inhaled Ag (L. Cohn, manuscript in preparation).
By generating Th2 cells in vitro in these studies we have eliminated
the problem of Th1 bias due to the in vivo priming environment and can
assess specifically the effector functions of Th2 cells and their
cytokines.
In IL-4R-/- mice, receptor signaling in
response to both IL-4 and IL-13 is inhibited (13, 15). The IL-4R
-chain associates with the c subunit to form the IL-4R or pairs
with IL-13R to form a distinct IL-13R. The common receptor chain and
signal transduction pathway are believed to be responsible for the
overlapping functions of IL-4 and IL-13. Both cytokines prime CD4 T
cells to become Th2 cells, stimulate Ig isotype switching to IgE, and
induce suppression of immune responses (30, 31, 37). In
IL-4R-/- mice there is no activation of
Stat6, Th2 cell differentiation, or IgE production (13, 15). Since
mucus can be stimulated in the absence of IL-4, and there is complete
inhibition of mucus production in IL-4R-/-
mice, one possible interpretation is that IL-13 is essential to
activate the airway epithelium in the absence of IL-4. In studies
published while this manuscript was in review, IL-13 was shown to play
an important role in mucus production. In OVA-immunized,
aerosol-challenged mice that were treated with an IL-13 inhibitor,
goblet cell mucus staining was markedly decreased (38, 39).
Furthermore, aerosol administration of IL-13 led to mucus induction.
Because IL-4 and IL-13 appear to be coordinately regulated (40), it is
not clear whether IL-4 alone can stimulate mucus production in the
absence of IL-13. Although many redundant functions of IL-4 and IL-13
have been reported (41), there are clear examples of cytokine-specific
responses. Recently, IL-13, but not IL-4, was identified as essential
for worm expulsion in parasitic nematode infection (30, 42, 43), and
differential epithelial cell responses to these cytokines have been
described (44). Whether IL-4 and IL-13 have identical functions in the
induction of mucus production awaits further study.
Eosinophil activation in the airways is associated with mucus production in both humans and animals. Eosinophil cationic protein has been shown to stimulate mucus production, as have other mediators from eosinophils that are released during activation (3). Yet, we have shown that eosinophils are not required for mucus induction by Th2 cells. Since there is no reduction in mucus production as airway eosinophils are progressively eliminated from the lung, eosinophils cannot contribute to mucus induction in this experimental system. Therefore, it is likely that the association of eosinophils and mucus production seen in mice is merely an association of eosinophils with activated Th2 cells secreting IL-5.
Mast cells are activated by IgE, have receptors for IL-4 and IL-13, express mRNA for IL-4 and IL-13, and thus may contribute to Th2 inflammation (27, 28, 29). Once activated, mast cells secrete a variety of mediators known to be mucus secretagogues, including histamine, leukotrienes, and platelet-activating factor (3). In systemically immunized and aerosol-challenged mast cell-deficient mice, Kung et al. showed a 60% reduction in airway eosinophilia, suggesting that Th2 responses were decreased in the absence of mast cells (45), while others showed that mast cells did not contribute to eosinophilia or airway hyper-responsiveness (46, 47). Thus, we wanted to test whether mast cells contributed to Th2-induced mucus production. W/Wv mice are genetically deficient in mast cells, showing <1% of mast cells at mucosal surfaces and no staining of mast cells in the airway submucosa (47, 48, 49). In our studies mast cell-deficient and wild-type mice that received Th2 cells and inhaled Ag had similar inflammatory responses. Both airway eosinophilia (not shown) and mucus production were equivalent. The reduction in eosinophils seen previously probably results either from a defect in Th2 cell priming in the absence of mast cells or from an effector mechanism that is evident only when inflammation is mild. However, these studies show definitively that Th2 cells can stimulate mucus production in the absence of mast cell-derived mediators.
IL-13 and/or IL-4 stimulate mucus production either by direct effects
on mucus-secreting goblet cells or indirectly through mediators
activated locally in the lung. Mucus is a mixture of proteins, mucus
glycoproteins, glycosaminoglycans, water, and electrolytes that lines
the upper and lower airways. Mucins, five of which have been shown to
be expressed in the respiratory tract, are a heterogeneous group of
richly glycosylated molecules secreted by epithelial cells that give
mucus its viscous property (50). The mechanisms by which inflammatory
stimuli lead to increased epithelial mucin production are unknown.
IL-4R may signal an initial step in Th2-induced mucus production.
Understanding these mechanisms may contribute significantly to our
ability to reduce the morbidity from asthma.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. L. Cohn, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar St., P.O. Box 208057, New Haven, CT 06520-8057. E-mail address:
3 Abbreviations used in this paper: pOVA323–339, OVA peptide 323–339; BAL, bronchoalveolar lavage; PAS, periodic acid-Schiff; HMI, histologic mucus index.
4 M. Mohrs, B. Ledermann, G. Koehler, A. Dorfmuller, A. Gessner, F. Brombacher. Differences between IL-4 and IL-4R deficient mice reveal a protective role for IL-13 receptor signaling in chronic Leishmania major infection. Submitted for publication.
Received for publication November 25, 1998. Accepted for publication February 22, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-deficient and IL-4-deficient mice reveal a role for IL-13 in the regulation of Th2 responses. Curr. Biol. 8:669.[Medline]
RI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J. Clin. Invest. 99:1492.[Medline]
, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 8:255.[Medline]
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A. E. Kelly-Welch, M. E. F. Melo, E. Smith, A. Q. Ford, C. Haudenschild, N. Noben-Trauth, and A. D. Keegan Complex Role of the IL-4 Receptor {alpha} in a Murine Model of Airway Inflammation: Expression of the IL-4 Receptor {alpha} on Nonlymphoid Cells of Bone Marrow Origin Contributes to Severity of Inflammation J. Immunol., April 1, 2004; 172(7): 4545 - 4555. [Abstract] [Full Text] [PDF]
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E. A. B. Kelly and W. W. Busse Who Is Captain of the Inflammatory Ship in Asthma? Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 551 - 552. [Full Text] [PDF]
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M. A. Aronica, S. McCarthy, S. Swaidani, D. Mitchell, M. Goral, J. R. Sheller, and M. Boothby Recall Helper T Cell Response: T Helper 1 Cell-resistant Allergic Susceptibility without Biasing Uncommitted CD4 T Cells Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 587 - 595. [Abstract] [Full Text] [PDF]
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N. Miyahara, K. Takeda, T. Kodama, A. Joetham, C. Taube, J.-W. Park, S. Miyahara, A. Balhorn, A. Dakhama, and E. W. Gelfand Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13 J. Immunol., February 15, 2004; 172(4): 2549 - 2558. [Abstract] [Full Text] [PDF]
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 L. J. V. Galietta, C. Folli, E. Caci, N. Pedemonte, A. Taddei, R. Ravazzolo, and O. Zegarra-Moran Effect of Inflammatory Stimuli on Airway Ion Transport Proceedings of the ATS, January 1, 2004; 1(1): 62 - 65. [Abstract] [Full Text] [PDF]
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D. Rodriguez, A. C. Keller, E. L. Faquim-Mauro, M. S. de Macedo, F. Q. Cunha, J. Lefort, B. B. Vargaftig, and M. Russo Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity J. Immunol., July 15, 2003; 171(2): 1001 - 1008. [Abstract] [Full Text] [PDF]
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J. R. Reader, D. M. Hyde, E. S. Schelegle, M. C. Aldrich, A. M. Stoddard, M. P. McLane, R. C. Levitt, and J. S. Tepper Interleukin-9 Induces Mucous Cell Metaplasia Independent of Inflammation Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 664 - 672. [Abstract] [Full Text] [PDF]
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R. T. Strait, S. C. Morris, K. Smiley, J. F. Urban Jr., and F. D. Finkelman IL-4 Exacerbates Anaphylaxis J. Immunol., April 1, 2003; 170(7): 3835 - 3842. [Abstract] [Full Text] [PDF]
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H. H. Shen, S. I. Ochkur, M. P. McGarry, J. R. Crosby, E. M. Hines, M. T. Borchers, H. Wang, T. L. Biechelle, K. R. O'Neill, T. L. Ansay, et al. A Causative Relationship Exists Between Eosinophils and the Development of Allergic Pulmonary Pathologies in the Mouse J. Immunol., March 15, 2003; 170(6): 3296 - 3305. [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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J. P. Justice, M. T. Borchers, J. R. Crosby, E. M. Hines, H. H. Shen, S. I. Ochkur, M. P. McGarry, N. A. Lee, and J. J. Lee Ablation of eosinophils leads to a reduction of allergen-induced pulmonary pathology Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L169 - L178. [Abstract] [Full Text] [PDF]
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 J. V. Fahy Goblet Cell and Mucin Gene Abnormalities in Asthma Chest, December 1, 2002; 122 (2009): 320S - 326S. [Abstract] [Full Text] [PDF]
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R. Stephens and D. D. Chaplin IgE Cross-Linking or Lipopolysaccharide Treatment Induces Recruitment of Th2 Cells to the Lung in the Absence of Specific Antigen J. Immunol., November 15, 2002; 169(10): 5468 - 5476. [Abstract] [Full Text] [PDF]
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F. Kheradmand, A. Kiss, J. Xu, S.-H. Lee, P. E. Kolattukudy, and D. B. Corry A Protease-Activated Pathway Underlying Th Cell Type 2 Activation and Allergic Lung Disease J. Immunol., November 15, 2002; 169(10): 5904 - 5911. [Abstract] [Full Text] [PDF]
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Y. Tesfaigzi, M. J. Fischer, M. Daheshia, F. H. Y. Green, G. T. De Sanctis, and J. A. Wilder Bax is Crucial for IFN-{gamma}-Induced Resolution of Allergen- Induced Mucus Cell Metaplasia J. Immunol., November 15, 2002; 169(10): 5919 - 5925. [Abstract] [Full Text] [PDF]
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M. Kondo, J. Tamaoki, K. Takeyama, J. Nakata, and A. Nagai Interleukin-13 Induces Goblet Cell Differentiation in Primary Cell Culture from Guinea Pig Tracheal Epithelium Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 536 - 541. [Abstract] [Full Text] [PDF]
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L. Whittaker, N. Niu, U.-A. Temann, A. Stoddard, R. A. Flavell, A. Ray, R. J. Homer, and L. Cohn Interleukin-13 Mediates a Fundamental Pathway for Airway Epithelial Mucus Induced by CD4 T Cells and Interleukin-9 Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 593 - 602. [Abstract] [Full Text] [PDF]
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N.J. Vanacker, E. Palmans, R.A. Pauwels, and J.C. Kips Dose-related effect of inhaled fluticasone on allergen-induced airway changes in rats Eur. Respir. J., October 1, 2002; 20(4): 873 - 879. [Abstract] [Full Text] [PDF]
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 C. G. Lee, R. J. Homer, L. Cohn, H. Link, S. Jung, J. E. Craft, B. S. Graham, T. R. Johnson, and J. A. Elias Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways J. Biol. Chem., September 13, 2002; 277(38): 35466 - 35474. [Abstract] [Full Text] [PDF]
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 J. G. Wagner, J. A. Hotchkiss, and J. R. Harkema Enhancement of Nasal Inflammatory and Epithelial Responses after Ozone and Allergen Coexposure in Brown Norway Rats Toxicol. Sci., June 1, 2002; 67(2): 284 - 294. [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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L. J. V. Galietta, P. Pagesy, C. Folli, E. Caci, L. Romio, B. Costes, E. Nicolis, G. Cabrini, M. Goossens, R. Ravazzolo, et al. IL-4 Is a Potent Modulator of Ion Transport in the Human Bronchial Epithelium In Vitro J. Immunol., January 15, 2002; 168(2): 839 - 845. [Abstract] [Full Text] [PDF]
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M. Singer, J. Lefort, and B. B. Vargaftig Granulocyte Depletion and Dexamethasone Differentially Modulate Airways Hyperreactivity, Inflammation, Mucus Accumulation, and Secretion Induced by rmIL-13 or Antigen Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 74 - 84. [Abstract] [Full Text] [PDF]
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A. KANEHIRO, M. LAHN, M. J. MAKELA, A. DAKHAMA, M. FUJITA, A. JOETHAM, R. J. MASON, W. BORN, and E. W. GELFAND Tumor Necrosis Factor-alpha Negatively Regulates Airway Hyperresponsiveness through gamma delta T Cells Am. J. Respir. Crit. Care Med., December 15, 2001; 164(12): 2229 - 2238. [Abstract] [Full Text] [PDF]
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K. Blease, C. Jakubzick, J. M. Schuh, B. H. Joshi, R. K. Puri, and C. M. Hogaboam IL-13 Fusion Cytotoxin Ameliorates Chronic Fungal-Induced Allergic Airway Disease in Mice J. Immunol., December 1, 2001; 167(11): 6583 - 6592. [Abstract] [Full Text] [PDF]
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K.-I. HASHIMOTO, Y. ISHII, Y. UCHIDA, T. KIMURA, K. MASUYAMA, Y. MORISHIMA, K. HIRANO, A. NOMURA, T. SAKAMOTO, H. TAKANO, et al. Exposure to Diesel Exhaust Exacerbates Allergen-induced Airway Responses in Guinea Pigs Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1957 - 1963. [Abstract] [Full Text] [PDF]
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J. V. FAHY Remodeling of the Airway Epithelium in Asthma Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): S46 - 51. [Abstract] [Full Text] [PDF]
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P.-R. Burgel, S. C. Lazarus, D. C.-W. Tam, I. F. Ueki, K. Atabai, M. Birch, and J. A. Nadel Human Eosinophils Induce Mucin Production in Airway Epithelial Cells Via Epidermal Growth Factor Receptor Activation J. Immunol., November 15, 2001; 167(10): 5948 - 5954. [Abstract] [Full Text] [PDF]
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D. M. Walter, J. J. McIntire, G. Berry, A. N. J. McKenzie, D. D. Donaldson, R. H. DeKruyff, and D. T. Umetsu Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity J. Immunol., October 15, 2001; 167(8): 4668 - 4675. [Abstract] [Full Text] [PDF]
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M. Yang, S. P. Hogan, P. J. Henry, K. I. Matthaei, A. N. J. McKenzie, I. G. Young, M. E. Rothenberg, and P. S. Foster Interleukin-13 Mediates Airways Hyperreactivity through the IL-4 Receptor-Alpha Chain and STAT-6 Independently of IL-5 and Eotaxin Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 522 - 530. [Abstract] [Full Text] [PDF]
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A. Wensky, M. C. Garibaldi Marcondes, and J. J. Lafaille The Role of IFN-{gamma} in the Production of Th2 Subpopulations: Implications for Variable Th2-Mediated Pathologies in Autoimmunity J. Immunol., September 15, 2001; 167(6): 3074 - 3081. [Abstract] [Full Text] [PDF]
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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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A. Takaoka, Y. Tanaka, T. Tsuji, T. Jinushi, A. Hoshino, Y. Asakura, Y. Mita, K. Watanabe, S. Nakaike, Y. Togashi, et al. A Critical Role for Mouse CXC Chemokine(s) in Pulmonary Neutrophilia During Th Type 1-Dependent Airway Inflammation J. Immunol., August 15, 2001; 167(4): 2349 - 2353. [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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 B. Deplancke and H R. Gaskins Microbial modulation of innate defense: goblet cells and the intestinal mucus layer Am. J. Clinical Nutrition, June 1, 2001; 73 (6): 1131S - 1141S. [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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M. Russo, M.-A. Nahori, J. Lefort, E. Gomes, A. de Castro Keller, D. Rodriguez, O. G. Ribeiro, S. Adriouch, V. Gallois, A. M. C. de Faria, et al. Suppression of Asthma-like Responses in Different Mouse Strains by Oral Tolerance Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 518 - 526. [Abstract] [Full Text]
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C. Bandeira-Melo, K. Sugiyama, L. J. Woods, and P. F. Weller Cutting Edge: Eotaxin Elicits Rapid Vesicular Transport-Mediated Release of Preformed IL-4 from Human Eosinophils J. Immunol., April 15, 2001; 166(8): 4813 - 4817. [Abstract] [Full Text] [PDF]
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 A. G.-H. Jember, R. Zuberi, F.-T. Liu, and M. Croft Development of Allergic Inflammation in a Murine Model of Asthma Is Dependent on the Costimulatory Receptor Ox40 J. Exp. Med., February 5, 2001; 193(3): 387 - 392. [Abstract] [Full Text] [PDF]
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J. J. Shim, K. Dabbagh, I. F. Ueki, T. Dao-Pick, P.-R. Burgel, K. Takeyama, D. C.-W. Tam, and J. A. Nadel IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L134 - L140. [Abstract] [Full Text] [PDF]
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Y. Tesfaigzi, M. J. Fischer, A. J. Martin, and J. Seagrave Bcl-2 in LPS- and allergen-induced hyperplastic mucous cells in airway epithelia of Brown Norway rats Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1210 - L1217. [Abstract] [Full Text] [PDF]
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C.-H. Chen, D.-H. Zhang, J. M. LaPorte, and A. Ray Cyclic AMP Activates p38 Mitogen-Activated Protein Kinase in Th2 Cells: Phosphorylation of GATA-3 and Stimulation of Th2 Cytokine Gene Expression J. Immunol., November 15, 2000; 165(10): 5597 - 5605. [Abstract] [Full Text] [PDF]
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A. KANEHIRO, K. TAKEDA, A. JOETHAM, A. TOMKINSON, T. IKEMURA, C. G. IRVIN, and E. W. GELFAND Timing of Administration of Anti-VLA-4 Differentiates Airway Hyperresponsiveness in the Central and Peripheral Airways in Mice Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 1132 - 1139. [Abstract] [Full Text]
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J. Wang, R. J. Homer, L. Hong, L. Cohn, C. G. Lee, S. Jung, and J. A. Elias IL-11 Selectively Inhibits Aeroallergen-Induced Pulmonary Eosinophilia and Th2 Cytokine Production J. Immunol., August 15, 2000; 165(4): 2222 - 2231. [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. Wills-Karp Trophic Slime, Allergic Slime Am. J. Respir. Cell Mol. Biol., June 1, 2000; 22(6): 637 - 639. [Full Text]
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N. M. Munoz, G. A. van Seventer, R. T. Semnani, and A. R. Leff Augmentation of LTC4 synthesis in human eosinophils caused by CD3-stimulated Th2-like cells in vitro Am J Physiol Lung Cell Mol Physiol, June 1, 2000; 278(6): L1172 - L1179. [Abstract] [Full Text] [PDF]
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C. M. Lloyd, T. Delaney, T. Nguyen, J. Tian, C. Martinez-A, A. J. Coyle, and J.-C. Gutierrez-Ramos Cc Chemokine Receptor (Ccr)3/Eotaxin Is Followed by Ccr4/Monocyte-Derived Chemokine in Mediating Pulmonary T Helper Lymphocyte Type 2 Recruitment after Serial Antigen Challenge in Vivo J. Exp. Med., January 17, 2000; 191(2): 265 - 274. [Abstract] [Full Text] [PDF]
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L. Cohn, R. J. Homer, N. Niu, and K. Bottomly T Helper 1 Cells and Interferon {gamma} Regulate Allergic Airway Inflammation and Mucus Production J. Exp. Med., November 1, 1999; 190(9): 1309 - 1318. [Abstract] [Full Text] [PDF]
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Z. Zhu, B. Ma, R. J. Homer, T. Zheng, and J. A. Elias Use of the Tetracycline-controlled Transcriptional Silencer (tTS) to Eliminate Transgene Leak in Inducible Overexpression Transgenic Mice J. Biol. Chem., June 29, 2001; 276(27): 25222 - 25229. [Abstract] [Full Text] [PDF]
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J. P. Justice, J. Crosby, M. T. Borchers, A. Tomkinson, J. J. Lee, and N. A. Lee CD4+ T cell-dependent airway mucus production occurs in response to IL-5 expression in lung Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L1066 - L1074. [Abstract] [Full Text] [PDF]
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