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*
Division of Immunology and Allergy, Department of Pediatrics, and
Department of Pathology, Stanford University, Stanford, CA 94305;
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom; and
Immunology Department, Genetics Institute, Cambridge, MA 02140
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c-ByJ mice were obtained from The Jackson Laboratory (Bar Harbor, ME). IL-13-/- mice were generated from 129 x C57BL/6 mice, with the disruption in exon 1 (10), and were backcrossed for seven generations onto the BALB/c strain. IL-4-/-/IL-13-/- mice were generated from 129 x C57BL/6 mice (11) that were backcrossed for seven generations onto the BALB/c strain. DO11.10 mice, which are transgenic for TCR recognizing OVA peptide 323–339 and backcrossed to BALB/c were kindly provided by Dr. D. Loh and were bred in our facilities. DO11.10/IL13-/- were generated by crossing IL-13-/- mice with DO11.10 mice and backcrossing the F1 progeny (IL-13+/-/DO11.10+/-) to IL-13-/- mice. The resulting N2 progeny were screened by PCR to identify IL-13-/- mice. The IL-13-/- mice were then screened by flow cytometry for mice containing CD4+, KJ1-26 TCR+ cells. These mice were termed DO11.10/IL13-/- mice. Animals were used between 7 and 12 wk of age and were age and sex matched within each experiment. The Stanford University Committee on Animal Welfare approved all animal protocols.
Monoclonal Abs
mAbs were purified from ascites fluid by ammonium sulfate
precipitation and ion exchange chromatography. We used the following
hybridomas: R46A2 (anti-IFN-
mAb), obtained from American Type
Culture Collection (Manassas, VA); XMG1.2 (anti-IFN- mAb),
generously provided by Dr. T. Mosmann (University of Rochester, NY);
BVD4-1D11 (anti-IL-4), and BVD6-24G2 (anti-IL-4 mAb), obtained
from Dr. M. Howard (Corixa, Redwood City, CA); C17.8 (anti-IL-12
mAb), obtained from Dr. G. Trinchieri (Schering-Plough Laboratory of
Immunological Research, Dardilly, France); EM95 (rat
anti-mouse IgE mAb), kindly provided by Dr. R. Coffman (DNAX
Research Institute, Palo Alto, CA). Anti-OVA mAbs were produced as
described previously (12). Anti-38C13 idiotype mAb 4G10
(rat IgG2a) (13) was used as control. Hybridoma cells
producing the anti-clonotypic Ab KJ1-26 were provided by Dr. P.
Marrack (National Jewish Medical Center, Denver, CO).
Immunization protocols
BALB/c (IL-13+/+) or
IL-13-/- mice were sensitized to OVA using an
established protocol for the induction of AHR in BALB/c mice
(14). Briefly, 50 µg OVA adsorbed to 2 mg aluminum
potassium sulfate (alum) were administered i.p. to
IL-13+/+ or IL-13-/- on
day zero. On day 14, 50 µg OVA in alum was given i.p., and 50 µg
OVA in 50 µl normal saline were administered intranasally (i.n.). On
days 25, 26, and 27, the mice were boosted again with OVA i.n. One day
after the last intranasal challenge (day 28), AHR was measured in
conscious mice after inhalation of increasing concentrations of
methacholine (see below). Two days after the last challenge (day 29),
mice were bled and then sacrificed, lungs were removed for histology,
and bronchial lymph nodes were isolated for in vitro culture. For
experiments in Figs. 4
and 5, a shorter, but comparable, established
immunization protocol was used (15). OVA (50 µg adsorbed
to alum) was administered i.p on day 0. On days 7, 8, and 9, 50 µg
OVA in 50 µl normal saline were given i.n. Control mice received i.p.
injections of alum alone and OVA i.n. as described above. AHR was
measured 1 day later (day 10). On day 11, mice were bled and then
sacrificed as described above.
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OVA-specific Th2 lines were generated from spleen of DO11.10 (OVA TCR transgenic) IL13+/+ mice and DO11.10 IL13-/- mice. T cells were purified from spleen by negative selection on anti-Ig-coated plates, followed by positive selection using MACS CD4 microbeads (Miltenyi Biotec, Auburn, CA). T cells were cultured at 5 x 105/well with 4 x 106 irradiated spleen cells as APCs and OVA (50 µg/ml; Sigma, St. Louis, MO). To generate Th2 lines, rIL-4 (4 ng/ml) and anti-IL-12 mAb (10 µg/ml) were added to the cultures. After 7 days, cells were washed, counted, and restimulated at 3 x 105/well with APC and Ag, under the same conditions used for the initial stimulation. Th cell lines were used for transfer into SCID mice 7 days after restimulation. The cytokine profiles of the Th2 lines were confirmed by direct examination of Con A supernatants generated from these lines on the day of transfer, using ELISA.
Transfer of OVA-specific Th2 cells
Th2 cell lines were transferred into histocompatible SCID mice. To facilitate homing of the T cell lines to the lungs, SCID mice were given 50 µg OVA in 50 µl normal saline i.n.1 day before i.v. transfer of cells. Cultured Th2 cells were harvested and washed with PBS, and 2.5 x 106 cells were adoptively transferred i.v. into the mice. Control mice received only i.n. OVA. One and 2 days after the adoptive transfer of cells, OVA was again administered i.n. AHR was determined 24 h after the last i.n. dose of Ag was administered.
Treatment of mice with anti-cytokine and depletion mAb
Mice undergoing sensitization to OVA were injected i.p. with 1
mg mAb XMG1.2 (for IFN- depletion) every 5 days, starting 1 day
before administration of OVA i.p. The Abs were present throughout the
course of immunization and assessment of AHR.
Treatment of mice with rIL-13
Purified rIL-13 (7) was administered i.n. to
IL-13-/- mice to determine whether it would
restore the development of AHR. Mice undergoing sensitization to OVA
with were given 2 µg rIL-13 i.n. on days 7, 8, and 9 in 50 µl
normal saline with or without 50 µg OVA (Fig. 4
B). Naive
mice were given 2 µg rIL-13 i.n. for 3 consecutive days in 50 µl
normal saline before measuring AHR on the 4th day.
Measurement of AHR
AHR was assessed by methacholine-induced airflow obstruction from conscious mice placed in a whole body plethysmograph (model PLY 3211; Buxco Electronics, Troy, NY), as described previously (14).
Determination of lung histology
Animals were sacrificed by CO2 asphyxiation. The lungs were removed, washed in PBS, inflated, and fixed in 10% neutral buffered formalin, sectioned 5 µm thick, routinely processed, embedded in paraffin wax, and stained with H&E. Intracytoplasmic and luminal mucin was assessed by periodic acid-Schiff (PAS) and predigested PAS stains.
Restimulation of lymph node cells in vitro
Cells (3.0 x 106 in a 24-well plate,
for cytokine ELISAs or 5.0 x 105 in a
96-well plate, for proliferation) isolated from bronchial lymph nodes
were restimulated in vitro in the presence or absence of 100 µg/ml
OVA. For ELISA, supernatants were harvested after 4 days for
determination of IL-4, IL-5, IL-13, and IFN- levels. For
proliferation, cultures were incubated for 4 days and pulsed with 1
µCi [3H]thymidine for the last 18
h.
Cytokine ELISAs
ELISAs were performed as previously described (16).
The mAb pairs used were as follows, listed by capture/biotinylated
detection mAb: IFN-, R4-6A2/XMG1.2; IL-4, 11B11/BVD6-24G2; IL-12,
C17.8/C15.6; IL-5, TRFK5/TRFK4. Reagents for detection of murine IL-13
were purchased from R&D Systems (Minneapolis, MN).
OVA-specific Igs assay
Mice were bled, and serum levels of OVA-specific IgG1, IgG2a, and IgE Abs were measured using modified OVA-specific ELISAs as previously described (17). Anti-OVA IgG1 and IgG2a mAbs 6C1 and 3A11, respectively, were used as standards for the quantification of each IgG subclass. The standard for the OVA-specific IgE ELISA was sera from mice hyperimmunized with OVA that had been quantitated for IgE.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the role of IL-13 in the development of
allergen-induced AHR, we sensitized and challenged
IL-13-/-,
IL-4-/-/IL-13-/-, and
IL-4-/- mice with OVA using a standard
protocol. Fig. 1A demonstrates
that control wild-type IL-13+/+ mice sensitized
and challenged i.n. with OVA developed significant AHR, elicited with
increasing concentration of methacholine. However,
IL-13-/- mice sensitized and challenged in the
same manner with OVA had almost normal airway responsiveness. In
contrast, sensitization and challenge of
IL-4-/- mice resulted in significant AHR, as we
have previously reported (18). In some experiments, as
shown in Fig. 1, the degree of AHR that developed in the
IL-4-/- mice was slightly less than that
observed in wild-type mice, suggesting that IL-4 might play a minor
role in the development of AHR. In contrast, mice that lacked both IL-4
and IL-13
(IL-4-/-/IL-13-/-) when
sensitized and challenged with OVA had normal airway reactivity (Fig. 1B). Control wild-type IL-13+/+ mice
that received OVA i.n. without prior sensitization with OVA in alum
i.p., as expected, did not develop AHR (Fig. 1), nor did mice that
received i.n. saline develop AHR (data not shown). These results
indicated that the presence of IL-13, but not IL-4, was critical for
the development of AHR.
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The failure of IL-13-/- mice to develop
AHR was not due to the inability these mice to develop airway
inflammation. Examination of tissues taken from the lungs of
OVA-sensitized and -challenged IL-13-/- mice
had intense airway inflammation, with significant eosinophilia (Fig. 2B). Mucus production,
however, was greatly reduced in the IL-13-/-
mice, as reflected by a great reduction in the epithelial cell
cytoplasmic content, and reduced PAS (magenta) staining for mucus (Fig. 2B, insets). In contrast, airway inflammation in wild-type
IL-13+/+ mice sensitized and challenged with OVA
was intense with significant eosinophilia as well as mucus production
(Fig. 2A). The
IL-4-/-/IL-13-/- mice
sensitized and challenged with OVA had essentially normal lung
histology (Fig. 2C), as did control
IL-13-/- mice that received i.n. OVA without
prior sensitization to OVA (Fig. 2D), whereas
IL-4-/- mice sensitized and challenged with OVA
developed significant airway inflammation and mucus production (Fig. 2E). These results together indicated that the intense
airway inflammation with eosinophilia that developed in
IL-13-/- mice was not sufficient for the
induction of AHR and that IL-13, but not IL-4, was required for the
development of AHR.
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We examined the cytokines produced in bronchial lymph node cells
in IL-13-/- mice sensitized and challenged with
OVA. Fig. 3A shows that lymph
node cells from all mice sensitized and challenged with i.n. OVA
proliferated vigorously in response to OVA. The proliferating T cells
from wild-type IL-13+/+ mice produced substantial
quantities of IL-13, as well as large quantities of IL-4 and IL-5, but
no detectable IFN-. The T cells from OVA sensitized and challenged
IL-13-/- mice developed a similar Th2 profile
with high levels of IL-4 and IL-5 but, as expected, no IL-13. The Th2
response in these IL-13-/- mice was associated
with the production of OVA-specific IgE and IgG1, although these levels
were slightly lower that that observed in wild-type
IL-13+/+ mice (Fig. 3B). In addition,
T cells from IL-13-/- mice sensitized and
challenged with OVA produced detectable levels of IFN-. In contrast,
T cells from
IL-4-/-/IL-13-/- mice
sensitized and challenged with OVA produced low levels of IFN- and
IL-5 and no IL-4 or IL-13. This was associated with production of
background levels of OVA-specific IgE but increased amounts of
OVA-specific IgG2a. Together these results indicated that the
OVA-sensitized and -challenged IL-13-/- mice
failed to develop AHR despite the generation of a polarized
OVA-specific Th2 response, associated with increased production of
OVA-specific IgE, and significant airway inflammation.
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do not develop AHR
Because OVA-sensitized and -challenged
IL-13-/- mice produced more IFN- than did
sensitized and challenged wild-type IL-13-/-
mice, we asked whether IL-13-/- mice could
develop AHR when the IFN- was neutralized. Therefore, we
administered a neutralizing anti-IFN- mAb during the
immunization protocol. As expected, OVA-sensitized and -challenged
IL-13+/+ mice developed significant AHR, whereas
IL-13-/- mice, similarly sensitized and
challenged, had almost normal airway reactivity (Fig. 4A). Treatment with the
anti-IFN- mAb failed to reverse the inability of
IL-13-/- mice to develop AHR. Treatment of OVA
sensitized and challenged IL-13+/+ mice with
anti-IFN- mAb had no significant effect on AHR (data not shown).
When bronchial lymph node cells from these mice were cultured in the
presence of OVA, cells from the anti-IFN--treated group showed
greatly reduced levels of IFN- production as compared with cells
from the untreated IL-13-/- mice. Levels of
IFN- were similar to those in the wild-type BALB/c control,
indicating that the anti-IFN- treatment inhibited the
development of IFN- production in the
IL-13-/- mice (data not shown). Production of
IL-4, IL-5, IL-12, and IL-13 was not affected by the anti-IFN-
treatment (data not shown). Thus, the development of AHR in
IL-13-/- mice was not inhibited by increased
IFN- production.
IL-13-/- mice treated with IL-13 develop AHR
To demonstrate that IL-13-/- mice could
develop AHR if exogenous IL-13 was provided, we administered rIL-13
during the immunization protocol. Fig. 4B shows that i.n.
administration of rIL-13 to IL-13-/- mice
induced the development of AHR, whether or not the mice were sensitized
with i.p. OVA (Fig. 4B). IL-13-/-
mice that received rIL-13 had approximately the same responsiveness to
methacholine as did IL-13+/+ mice that were
sensitized and challenged with OVA, whereas
IL-13-/- mice that did not receive exogenous
IL-13 failed to develop AHR. Similarly, naive
IL-13+/+, IL-13-/-, and
IL-4-/-/IL-13-/-
treated with rIL-13 i.n. developed severe AHR (Fig. 4C).
Although administration of rIL-13 to naive mice caused the development
of AHR, examination of their lung histology was remarkable for almost
total absence of cellular infiltration and mucus production (data not
shown). These data suggest that the administration of exogenous IL-13
can directly activate the pathway that leads to the development of AHR
and that this occurs independently of eosinophils, mucus production,
and IL-4 expression.
OVA-specific Th2 cell lines generated from IL-13-/- mice do not induce AHR
Because OVA-specific Th2 responses may not develop optimally in
vivo in IL-13-/- mice, we examined the capacity
of Th2 lines generated ex vivo from IL-13-/-
mice to induce AHR when adoptively transferred into SCID mice. The
OVA-specific Th2 lines were generated from
IL-13-/- mice backcrossed to OVA TCR-transgenic
(DO11.10) mice. Fig. 5A shows
that the cytokine profiles of these IL-13-/-
Th2 cell lines included high levels of IL-4 and IL-5, negligible levels
of IFN-, and no IL-13. This profile was similar to the profile of a
control Th2 cell line generated from IL-13+/+
DO11.10 mice, except for IL-13, which was produced in large quantities
by the wild-type Th2 line. Thus, except for the lack of IL-13
production in the DO11.10/IL13-/- cell line,
both cell lines had similar Th2-like cytokine profiles. Fig. 5B shows that adoptive transfer of the wild-type
OVA-specific Th2 cell line resulted in the development of severe AHR in
recipient mice. In contrast, mice that received the DO11.10
IL-13-/- Th2 cell line failed to develop AHR.
The inability of the DO11.10 IL-13-/- Th2 cell
line to induce AHR was not due to a complete lack of functional
activity, because the IL-13-/- Th2 cell line
induced airway inflammation, consisting of eosinophils and lymphocytes
(Fig. 6). However, mucus production
induced by the IL-13-/- Th2 cell line was
greatly limited compared with that induced by the wild-type Th2 line.
In contrast, the degree of mononuclear infiltration appeared to be
equivalent between the two cell lines, suggesting that the DO11.10
IL-13-/- Th2 cells migrated to the lungs as
well as did the wild-type DO11.10 Th2 cells. These results using Th2
lines differing only in their production of IL-13 confirm our earlier
observations that OVA-sensitized and challenged
IL-13-/- mice do not develop AHR. These results
thus demonstrated that the AHR cannot develop in the absence of IL-13,
even in the presence of large quantities of other Th2 cytokines,
including IL-4 and IL-5, or in the presence of significant airway
eosinophilia.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies using IL-13-/- mice
backcrossed only five generations to BALB/c, demonstrated a modulatory
and proinflammatory role in airway inflammation for IL-13, the role of
which was thought to be redundant with IL-4 (9). In their
system with IL-13-/- mice, depletion of IL-5 or
IL-4 with neutralizing mAb was required to significantly diminish AHR.
Similarly, Grunig et al. (8) demonstrated that
administration of either rIL-13 or rIL-4 to rag 1-deficient mice
induced AHR, and the effects of these cytokines were mediated through
an IL-4 receptor 
-chain-dependent pathway. These studies,
demonstrating overlapping or complementary roles for IL-4 and IL-13 in
the induction of AHR, are consistent with those using STAT6-deficient
mice, which lack IL-4 and IL-13 signaling pathways and which do not
develop AHR (19, 20).
In our studies, however, using a slightly different protocol to induce AHR and using mice more completely backcrossed to BALB/c (seven generations), we showed that IL-13 alone was both necessary and sufficient for the development of AHR. We demonstrated that IL-4-/- mice have the capacity to develop significant AHR, indicating that although IL-4 contributes to the overall allergic inflammatory response and enhances eosinophil migration into the lungs (21), IL-4 is clearly not essential for the induction of AHR. We confirmed that administration of IL-13 to normal BALB/c mice induced AHR; in addition, we established that administration of IL-13 to IL-4/IL-13 double knockout mice induced AHR. Furthermore, the AHR in naive mice following i.n. administration of IL-13 developed independently of cellular infiltration and extensive mucus production. Moreover, we demonstrated that OVA-specific IL-13-/--derived Th2 cells, which produced high levels of IL-4 but not IL-13, were ineffective in inducing AHR. Together, our results using several distinct approaches and several different cytokine-deficient mice indicated that IL-13 in the absence of IL-4 induced AHR and that IL-4 in the absence of IL-13 did not.
IL-13 therefore plays a major role as an effector molecule in asthma.
Previous studies in humans demonstrated that IL-13 mRNA and protein
levels are elevated in the lungs of atopic and nonatopic asthmatics
(22, 23, 24), suggesting that overproduction of IL-13 may
predispose toward the development of both types of asthma
(23). In addition, human asthma has been linked to a
region of chromosome 5q and to polymorphisms in the IL-13 gene, which
is located at chromosome 5q32 (25, 26, 27, 28). Furthermore,
mutations in IL-4R, which is a component of the IL-13 receptor
complex, have been linked with asthma (29, 30). Taken
together, the mouse and human data suggest that IL-13 is an integral
component of the mosaic of factors that lead to the development of
asthma. It is clear, however, that there are many cytokines that play a
role in the development of asthma, and in contrast to our studies,
previous experiments in other laboratories have suggested that IL-5 as
well as IL-4 can induce AHR. Possible reasons for these conflicting
results include differences in the intensity of immunization and
challenge (more intensive regimens may bring out IL-13 independent
contributions), genetic modifiers in different murine strains, and
different methods used to measure airway responses. Nevertheless, our
results using a common mouse strain (BALB/c) and a standard method to
induce AHR indicate that IL-13 plays an essential role in the
development of AHR and suggest that antagonists of IL-13 may be
effective in the treatment of asthma in humans.
The precise mechanism by which IL-13 induces AHR is not clear. IL-13
may increase AHR by directly affecting airway smooth muscle cells.
IL-13 induces smooth muscle proliferation in vitro (31)
and can aid contractions of tracheal smooth muscle cells
(32). More recently, airway smooth muscle cells have been
shown to express IL-13 receptors, including both components of the
IL-13R complex (IL-13R1 and IL-4R) (25). In
addition, IL-13 may increase AHR by thickening airway walls because of
increased mucus secretion (33, 34). In this regard,
administration of IL-13 into the lungs of wild-type or
IL-4-/- mice induced mucus production (7, 8); in addition, transgenic mice overexpressing IL-13 had
increased mucus production (33, 34, 35). Moreover,
neutralization of IL-13 using a soluble IL-132-IgGFc fusion protein
reversed allergen-induced increases in mucus production
(7), and IL-13-/- mice had a
marked reduction in mucus secretion.
IL-13 may have several additional roles in asthma. For example, IL-13
may regulate cytokine synthesis and immune function, as evidenced by an
increase in IFN- production in IL-13-/-
mice, and through the production of IL-13 by NK T cells
(36). The increase in IFN- production in
IL-13-/- mice, however, cannot explain the
limited capacity of IL-13-/- mice to generate
AHR, because neutralization of IFN- did not restore AHR in these
mice. Serum IgE levels were slightly decreased in
IL-13-/- mice compared with wild-type mice and
was enhanced by anti-IFN- mAb treatment of these mice,
suggesting that IgE production was inhibited by increased IFN-
synthesis. Alternatively, IL-13 may normally serve to enhance IgE
synthesis, particularly because IL-13-/- mice
have previously been shown to have reduced serum levels of IgE
(10), and overexpression of IL-13 in transgenic mice
results in 10–100 fold higher levels of serum IgE levels (34, 35). Finally, IL-13 may have profibrotic activity, acting as a
key player in the development of hepatic fibrosis in vivo in normal
mice (37), and causing the accumulation of collagen in the
subepithelial layers in the lungs of mice overexpressing IL-13
(33, 34).
Our studies also demonstrated that in the absence of IL-13, airway inflammation and eosinophilia was insufficient to cause AHR. The role of eosinophils in causing AHR has been controversial but has been assumed to be a critical determinant of AHR (6, 38, 39, 40). However, several studies have shown that AHR can develop independently from the recruitment of eosinophils (4, 41, 42, 43, 44, 45, 46). In addition, it has been demonstrated that airway eosinophilia can occur without the development of AHR (7, 47). In contrast, T cells, rather than eosinophils, correlate directly with the development of AHR (7, 8, 45, 48, 49). Our results clearly show that T cells producing IL-13 are critical for the development of AHR, because transfer of IL-13+/+ Th2 cells but not IL-13-/- Th2 cells, induced the development of AHR.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dale T. Umetsu, Department of Pediatrics, Room G309, Stanford University, Stanford, CA 94305-5208. E-mail address: umetsu{at}stanford.edu
3 Abbreviations used in this paper: AHR, airway hyperreactivity; i.n., intranasal; PAS, periodic acid-Schiff; Penh, enhanced pause.
Received for publication June 4, 2001. Accepted for publication August 16, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, but not on eosinophils. J. Immunol. 162:6178. gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am. J. Hum. Genet. 66:517.[Medline]
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T. Koya, N. Miyahara, K. Takeda, S. Matsubara, H. Matsuda, C. Swasey, A. Balhorn, A. Dakhama, and E. W. Gelfand CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells J. Immunol., September 1, 2007; 179(5): 2787 - 2796. [Abstract] [Full Text] [PDF]
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Y. Ma, K. T. HayGlass, A. B. Becker, Y. Fan, X. Yang, S. Basu, G. Srinivasan, F. E. R. Simons, A. J. Halayko, and Z. Peng Novel Recombinant Interleukin-13 Peptide-based Vaccine Reduces Airway Allergic Inflammatory Responses in Mice Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 439 - 445. [Abstract] [Full Text] [PDF]
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A. Mishra, M. Wang, J. Schlotman, N. M. Nikolaidis, C. W. DeBrosse, M. L. Karow, and M. E. Rothenberg Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L305 - L313. [Abstract] [Full Text] [PDF]
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M. T. Kasaian, D. D. Donaldson, L. Tchistiakova, K. Marquette, X.-Y. Tan, A. Ahmed, B. A. Jacobson, A. Widom, T. A. Cook, X. Xu, et al. Efficacy of IL-13 Neutralization in a Sheep Model of Experimental Asthma Am. J. Respir. Cell Mol. Biol., March 1, 2007; 36(3): 368 - 376. [Abstract] [Full Text] [PDF]
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M. Koch, M. Witzenrath, C. Reuter, M. Herma, H. Schutte, N. Suttorp, H. Collins, and S. H. E. Kaufmann Role of Local Pulmonary IFN-{gamma} Expression in Murine Allergic Airway Inflammation Am. J. Respir. Cell Mol. Biol., August 1, 2006; 35(2): 211 - 219. [Abstract] [Full Text] [PDF]
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J. R. McDermott, N. E. Humphreys, S. P. Forman, D. D. Donaldson, and R. K. Grencis Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection J. Immunol., September 1, 2005; 175(5): 3207 - 3213. [Abstract] [Full Text] [PDF]
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S. Finotto, M. Hausding, A. Doganci, J. H. Maxeiner, H. A. Lehr, C. Luft, P. R. Galle, and L. H. Glimcher Asthmatic changes in mice lacking T-bet are mediated by IL-13 Int. Immunol., August 1, 2005; 17(8): 993 - 1007. [Abstract] [Full Text] [PDF]
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S. C. Fish, D. D. Donaldson, S. J. Goldman, C. M. M. Williams, and M. T. Kasaian IgE Generation and Mast Cell Effector Function in Mice Deficient in IL-4 and IL-13 J. Immunol., June 15, 2005; 174(12): 7716 - 7724. [Abstract] [Full Text] [PDF]
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F. D. Finkelman, M. Yang, C. Perkins, K. Schleifer, A. Sproles, J. Santeliz, J. A. Bernstein, M. E. Rothenberg, S. C. Morris, and M. Wills-Karp Suppressive Effect of IL-4 on IL-13-Induced Genes in Mouse Lung J. Immunol., April 15, 2005; 174(8): 4630 - 4638. [Abstract] [Full Text] [PDF]
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S.-Y. Eum, K. Maghni, B. Tolloczko, D. H. Eidelman, and J. G. Martin IL-13 may mediate allergen-induced hyperresponsiveness independently of IL-5 or eotaxin by effects on airway smooth muscle Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L576 - L584. [Abstract] [Full Text] [PDF]
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R. K. Kumar, C. Herbert, D. C. Webb, L. Li, and P. S. Foster Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma Am. J. Respir. Crit. Care Med., November 15, 2004; 170(10): 1043 - 1048. [Abstract] [Full Text] [PDF]
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C. Desmet, P. Gosset, B. Pajak, D. Cataldo, M. Bentires-Alj, P. Lekeux, and F. Bureau Selective Blockade of NF-{kappa}B Activity in Airway Immune Cells Inhibits the Effector Phase of Experimental Asthma J. Immunol., November 1, 2004; 173(9): 5766 - 5775. [Abstract] [Full Text] [PDF]
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A. Hoshino, T. Tsuji, J. Matsuzaki, T. Jinushi, S. Ashino, T. Teramura, K. Chamoto, Y. Tanaka, Y. Asakura, T. Sakurai, et al. STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation Int. Immunol., October 1, 2004; 16(10): 1497 - 1505. [Abstract] [Full Text] [PDF]
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D. Claveau, S. L. Chen, S. O'Keefe, D. M. Zaller, A. Styhler, S. Liu, Z. Huang, D. W. Nicholson, and J. A. Mancini Preferential Inhibition of T Helper 1, but Not T Helper 2, Cytokines in Vitro by L-826,141 [4-{2-(3,4-Bisdifluromethoxyphenyl)-2-{4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl}-3-methylpyridine-1-oxide], a Potent and Selective Phosphodiesterase 4 Inhibitor J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 752 - 760. [Abstract] [Full Text] [PDF]
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B. J. Marsland, T. J. Soos, G. Spath, D. R. Littman, and M. Kopf Protein Kinase C {theta} Is Critical for the Development of In Vivo T Helper (Th)2 Cell But Not Th1 Cell Responses J. Exp. Med., July 19, 2004; 200(2): 181 - 189. [Abstract] [Full Text] [PDF]
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D. A. Deshpande, S. Dogan, T. F. Walseth, S. M. Miller, Y. Amrani, R. A. Panettieri, and M. S. Kannan Modulation of Calcium Signaling by Interleukin-13 in Human Airway Smooth Muscle: Role of CD38/Cyclic Adenosine Diphosphate Ribose Pathway Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 36 - 42. [Abstract] [Full Text] [PDF]
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S. Ryzhov, A. E. Goldstein, A. Matafonov, D. Zeng, I. Biaggioni, and I. Feoktistov Adenosine-Activated Mast Cells Induce IgE Synthesis by B Lymphocytes: An A2B-Mediated Process Involving Th2 Cytokines IL-4 and IL-13 with Implications for Asthma J. Immunol., June 15, 2004; 172(12): 7726 - 7733. [Abstract] [Full Text] [PDF]
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C. Taube, X. Wei, C. H. Swasey, A. Joetham, S. Zarini, T. Lively, K. Takeda, J. Loader, N. Miyahara, T. Kodama, et al. Mast Cells, Fc{epsilon}RI, and IL-13 Are Required for Development of Airway Hyperresponsiveness after Aerosolized Allergen Exposure in the Absence of Adjuvant J. Immunol., May 15, 2004; 172(10): 6398 - 6406. [Abstract] [Full Text] [PDF]
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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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D. C. Webb, K. I. Matthaei, Y. Cai, A. N. J. McKenzie, and P. S. Foster Polymorphisms in IL-4R{alpha} Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13-/- Mice J. Immunol., January 15, 2004; 172(2): 1092 - 1098. [Abstract] [Full Text] [PDF]
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J.C. Kips, G.P. Anderson, J.J. Fredberg, U. Herz, M.D. Inman, M. Jordana, D.M. Kemeny, J. Lotvall, R.A. Pauwels, C.G. Plopper, et al. Murine models of asthma Eur. Respir. J., August 1, 2003; 22(2): 374 - 382. [Abstract] [Full Text] [PDF]
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M. A. Carey, D. R. Germolec, J. A. Bradbury, R. A. Gooch, M. P. Moorman, G. P. Flake, R. Langenbach, and D. C. Zeldin Accentuated T Helper Type 2 Airway Response after Allergen Challenge in Cyclooxygenase-1-/- but Not Cyclooxygenase-2-/- Mice Am. J. Respir. Crit. Care Med., June 1, 2003; 167(11): 1509 - 1515. [Abstract] [Full Text] [PDF]
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J. A. Elias, C. G. Lee, T. Zheng, Y. Shim, and Z. Zhu Interleukin-13 and Leukotrienes: An Intersection of Pathogenetic Schema Am. J. Respir. Cell Mol. Biol., April 1, 2003; 28(4): 401 - 404. [Full Text] [PDF]
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B. B. Vargaftig and M. Singer Leukotrienes Mediate Murine Bronchopulmonary Hyperreactivity, Inflammation, and Part of Mucosal Metaplasia and Tissue Injury Induced by Recombinant Murine Interleukin-13 Am. J. Respir. Cell Mol. Biol., April 1, 2003; 28(4): 410 - 419. [Abstract] [Full Text] [PDF]
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S. Nakae, Y. Komiyama, H. Yokoyama, A. Nambu, M. Umeda, M. Iwase, I. Homma, K. Sudo, R. Horai, M. Asano, et al. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response Int. Immunol., April 1, 2003; 15(4): 483 - 490. [Abstract] [Full Text] [PDF]
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A. N.J. McKenzie and P. G. Fallon Decoy Receptors in the Regulation of T Helper Cell Type 2 Responses J. Exp. Med., March 17, 2003; 197(6): 675 - 679. [Full Text] [PDF]
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M. G. Chiaramonte, M. Mentink-Kane, B. A. Jacobson, A. W. Cheever, M. J. Whitters, M. E.P. Goad, A. Wong, M. Collins, D. D. Donaldson, M. J. Grusby, et al. Regulation and Function of the Interleukin 13 Receptor {alpha} 2 During a T Helper Cell Type 2-dominant Immune Response J. Exp. Med., March 17, 2003; 197(6): 687 - 701. [Abstract] [Full Text] [PDF]
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C. A. Herrick, L. Xu, A. N. J. McKenzie, R. E. Tigelaar, and K. Bottomly IL-13 Is Necessary, Not Simply Sufficient, for Epicutaneously Induced Th2 Responses to Soluble Protein Antigen J. Immunol., March 1, 2003; 170(5): 2488 - 2495. [Abstract] [Full Text] [PDF]
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C. Schramm, U. Herz, J. Podlech, M. Protschka, S. Finotto, M. J. Reddehase, H. Kohler, P. R. Galle, A. W. Lohse, and M. Blessing TGF-{beta} Regulates Airway Responses Via T Cells J. Immunol., February 1, 2003; 170(3): 1313 - 1319. [Abstract] [Full Text] [PDF]
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W. M. Abraham Of Mice and Men Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 1 - 4. [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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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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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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A. M. Khan, O. Elidemir, C. E. Epstein, K. P. Lally, H. Xue, M. Blackburn, G. L. Larsen, and G. N. Colasurdo Meconium aspiration produces airway hyperresponsiveness and eosinophilic inflammation in a murine model Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L785 - L790. [Abstract] [Full Text] [PDF]
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M. E. H. Bashir, P. Andersen, I. J. Fuss, H. N. Shi, and C. Nagler-Anderson An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen J. Immunol., September 15, 2002; 169(6): 3284 - 3292. [Abstract] [Full Text] [PDF]
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T. Kohyama, T. A. Wyatt, X. Liu, F.-Q. Wen, T. Kobayashi, Q. Fang, H. J. Kim, and S. I. Rennard PGD2 Modulates Fibroblast-Mediated Native Collagen Gel Contraction Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 375 - 381. [Abstract] [Full Text] [PDF]
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Y. Shibata, T. Kamata, M. Kimura, M. Yamashita, C.-R. Wang, K. Murata, M. Miyazaki, M. Taniguchi, N. Watanabe, and T. Nakayama Ras Activation in T Cells Determines the Development of Antigen-Induced Airway Hyperresponsiveness and Eosinophilic Inflammation J. Immunol., August 15, 2002; 169(4): 2134 - 2140. [Abstract] [Full Text] [PDF]
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H. J. Kim, X. Liu, H. Wang, T. Kohyama, T. Kobayashi, F.-Q. Wen, D. J. Romberger, S. Abe, W. MacNee, I. Rahman, et al. Glutathione prevents inhibition of fibroblast-mediated collagen gel contraction by cigarette smoke Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L409 - L417. [Abstract] [Full Text] [PDF]
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) or medium only (
). Proliferation was then determined by
[3H]thymidine incorporation, and IL-4, IL-5, IL-13, and
IFN-