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*
Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia; and
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
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Abstract |
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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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subunit
is critical for the development of enhanced bronchial reactivity in
murine models of asthma (21, 22, 23, 24, 25). Thus, there appears to
be an IL-4-independent, but IL-4R-dependent mechanism for the
activation of Stat6 and the induction of AHR.
Recently, IL-13, which also stimulates the activation of Stat6 by
signal transduction through the IL-4R subunit, has been shown to
mediate AHR in the allergic lung (24, 26). However, there
appears to be a temporal relationship in the requirement for either
IL-4 or IL-13 for the development of AHR. Blockade of IL-13, but not
IL-4, before aeroallergen challenge is sufficient to attenuate AHR
(11, 24, 26). In addition, while these cytokines induce
similar physiological responses through their shared usage of the
IL-4R subunit, there are distinct mechanisms mediated by either
cytokine (reviewed in Ref. 27), and this is corroborated
by their different spatial and temporal patterns of expression
(28, 29). Therefore, it is likely that IL-4 may be key
regulator for the development of a Th2 phenotype during sensitization
(11), and that IL-13 may be more important for the
induction of AHR during allergen inhalation (24, 26).
However, the precise mechanism underlying IL-13-mediated AHR and its
integrated relationship with IL-4- and IL-5-mediated processes is
unclear. The induction of AHR in naive mice by rIL-13 has been shown to
correlate with eosinophil accumulation in the airways in a process
dependent on signaling through the IL-4R subunit (24).
In contrast, the role of IL-13 in the development of allergic AHR has
been suggested to be dissociated from eosinophilic inflammation, but
implicated in other pathophysiological manifestations of the asthmatic
phenotype (26). Notably, while neutralization of IL-13
during challenge has been shown to attenuate mucus hypersecretion
concomitantly with AHR (26), the intrinsic association of
this secretogogenic process with AHR is yet to be fully delineated.
In this investigation, we have employed
IL-13-/- mice to examine
the role of this cytokine and its integrated relationship with IL-4 and
IL-5 in the development of pulmonary eosinophilia, mucus
hypersecretion, and AHR. Our data suggest dual roles for IL-13: one
that is modulatory during sensitization and lymphocyte priming and one
that is proinflammatory during aeroallergen challenge. This latter
process appears redundant with respect to IL-4, suggesting that both
cytokines, or their common receptor subunit IL-4R, may need to be
targeted for successful therapeutic intervention.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-13-/- mice were generated from (129 x C57BL/6) mice (30) that were backcrossed for five generations onto the BALB/c strain. WT mice were obtained from a similar number of backcrosses of the same genetic background. Mice were sensitized at 6 wk of age by i.p. injection with 50 µg of OVA/1 mg Alhydrogel (CSL, Parkville, Australia) in 0.9% sterile saline. Nonsensitized mice received 1 mg of Alhydrogel in 0.9% saline (Sal). WT and IL-13-/- mice were also injected i.p. with either IL-4 Ab (1 mg of 11B11), IL-5 Ab (1 mg of TRFK5), or isotype control Ab (1 mg of ßGL113) 24 h before the i.p. injection with OVA or Sal and then weekly throughout the experimental period. Abs were administered in sterile saline. On days 12, 14, 16, and 18, all groups of mice were aeroallergen challenged with OVA, as previously described (12, 16). Twenty-four hours after the last challenge, AHR was measured, and then mice were sacrificed by cervical dislocation and the inflammation and morphological changes to the airways were characterized. Mice were treated according to Australian National University Animal Welfare guidelines and were housed in a specific pathogen-free facility.
Characterization of lung morphology and leukocytes in blood, tissue, and bronchoalveolar lavage fluid
Lung tissue representing the central (bronchi-bronchiole) and peripheral (alveoli) airways was fixed in 10% phosphate-buffered Formalin, sectioned, and stained with Alcian blue-periodic-acid Schiff for the enumeration of mucin-secreting cells or Carbol’s Chromotrope-Hematoxylin for the identification of eosinophils. Leukocytes in the blood, bronchoalveolar lavage fluid, and lung were identified by morphological criteria and quantified, as previously described (12, 16).
Measurement of AHR
Responsiveness to ß-methacholine was assessed in conscious, unrestrained mice by barometric plethysmography, using apparatus and software supplied by Buxco (Troy, NY). This system yields a dimensionless parameter known as enhanced pause (Penh), reflecting changes in waveform of the pressure signal from the plethysmography chamber combined with a timing comparison of early and late expiration. Measurement was performed essentially as previously described (31). Briefly, mice were placed in the plethysmograph chamber and exposed to an aerosol of water (baseline readings) and then cumulative concentrations of ß-methacholine ranging from 3.125 to 25 mg/ml. The aerosol was generated by an ultrasonic nebulizer and drawn through the chamber for 2 min. The inlet was then closed and Penh readings taken for 3 min and averaged. Values were reported as the percentage increase over baseline.
Measurement of cytokine production by peribronchial lymph nodes (PBLN)
Cells from the PBLN were isolated and stimulated with 1 mg/ml
OVA in mixed lymphocyte culture medium for 72 h, as described
previously (32). The concentration of IL-4, IL-5, and
IFN-
in the cell-free supernatants was measured with ELISA
(32). The concentration of IL-13 was also determined with
ELISA using the Abs AB-413-NA and AF-413-NA (R&D Systems, Minneapolis,
MN) and following the manufacturer’s recommendations. The sensitivity
of detection was 0.5 ng/ml for IL-5, IL-13, and IFN-, and 0.1 ng/ml
for IL-4.
Statistical analysis
The significance of differences between experimental groups was analyzed using Student’s unpaired t test. Values were reported as the mean ± SEM. Differences in means were considered significant if p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the requirement for IL-13 in the development of
allergic disease of the lung,
IL-13-/- and WT mice were
sensitized and aeroallergen challenged with OVA. Twenty-four hours
after the last challenge, airway responsiveness to ß-methacholine was
determined (Fig. 1
). Both groups of
sensitized mice developed AHR when compared with nonsensitized mice,
suggesting that IL-13 is not obligatory for the development of AHR. In
fact, IL-13-deficient mice demonstrated a heightened response relative
to WT mice. We next determined the influence of both IL-4 and IL-5 in
the processes underlying AHR in WT and
IL-13-/- mice. In
contrast to WT mice in which neutralization of IL-4 before
sensitization only moderately inhibited AHR (Fig. 1A),
similar neutralization of IL-4 in IL-13-deficient mice reduced
bronchial responsiveness to the level seen in nonsensitized
IL-13-/- mice (Fig. 1B). Similarly, neutralization of IL-5 in
IL-13-/- mice, but not in
WT mice, significantly reduced AHR compared with the isotype
control-treated mice. Thus, these data demonstrate that the AHR that
develops in response to sensitization in
IL-13-/- mice is
dependent on IL-4- and to a lesser extent IL-5-mediated processes.
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To elucidate the cytokine network underlying AHR, the production
of IL-4, IL-13, IL-5, and IFN- by in vitro Ag-stimulated PBLN cells
from OVA-sensitized and challenged WT and
IL-13-/- mice treated
with anti-IL-4, IL-5, or isotype control Abs was determined.
IL-13-/- mice produced
similar amounts of IL-4 and IL-5 when compared with WT mice (Fig. 2, A and B).
Interestingly, neutralization of IL-5 significantly reduced the
production of IL-4 in both WT and
IL-13-/- mice (Fig. 2A), suggesting that eosinophils may influence the
production of IL-4. In contrast to WT mice in which neutralization of
IL-4 reduced IL-5 production to near baseline levels, similar treatment
of IL-13-/- mice was less
effective at inhibiting the production of this cytokine (Fig. 2B), indicating that IL-4-independent cells may be an
important source of IL-5 in
IL-13-/- mice. In
addition, while neutralization of IL-4 in WT mice inhibited the
production of IL-13, significant levels persisted (Fig. 2C),
suggesting that IL-4-independent mechanisms may also contribute to the
production of this cytokine. A deficiency of IL-5 in WT mice had little
impact on IL-13 levels, indicating that eosinophils are not associated
with the production of this cytokine, at least in the PBLN. No
Ag-specific production of IFN- could be detected in any samples.
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The numbers of eosinophils in the vasculature, the
peribronchial/perivascular region, and the airway lumen were determined
to assess the relationship between AHR and eosinophilia, and the role
of IL-4 and IL-13 in the recruitment of these cells. Sensitized and
challenged IL-13-/- mice
responded with a strong eosinophilia in the blood, tissue, and airway
compartments that was somewhat heightened, but paralleled the responses
seen in WT mice (Fig. 3). However, the
most apparent discrepancy between WT and
IL-13-/- mice was the
effect of neutralizing IL-4 on tissue eosinophilia (Fig. 3B). Although the deficiency of IL-4 in WT mice
significantly impaired the permeation of eosinophils into the airway
lumen (Fig. 3C), the development of tissue eosinophilia was
unchanged relative to IL-4-replete WT mice. This suggests that IL-4 may
provide an important signal in the permeation of eosinophils into the
airway lumen, and that the absence of eosinophils in this compartment
is not necessarily reflective of their tissue occupancy. In sharp
contrast, similar neutralization of IL-4 in
IL-13-/- mice inhibited
the accumulation of tissue eosinophils despite the development of a
pronounced blood eosinophilia (Fig. 3A). This indicates that
IL-4 and IL-13 elicit redundant responses associated with the
transendothelial migration of eosinophils. Notably, this low level of
tissue eosinophils correlated with a reduction in AHR in
IL-13-/- mice.
Neutralization of IL-5 in both WT and
IL-13-/- mice reduced the
levels of eosinophils in all compartments. However, in contrast to WT
mice, in which the inhibition of an IL-5-induced eosinophilia had no
effect on AHR, the low levels of this cell in the tissues of
IL-13-/- mice coincided
with a loss in bronchial hyperresponsiveness.
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Histological staining was used to determine the effect of Ag
stimulation on the hypersecretion of mucus in both WT and
IL-13-/- mice that were
treated with anti-IL-4 or isotype control Abs. In contrast to both
sensitized and challenged WT and IL-4-deficient mice, the numbers of
airway epithelial cells that stained positive for mucus were markedly
reduced in sensitized and challenged
IL-13-/- mice (Fig. 4). The concomitant depletion of IL-4 in
IL-13-/- mice did not
further reduce airway mucus production. Significantly, AHR persisted in
IL-13-/- mice, despite
substantially reduced mucus hypersecretion.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although neutralization of IL-13 during the airway challenge phase of
Ag exposure has been shown to limit AHR (24, 26), we have
demonstrated in the present study that AHR develops independently of
this cytokine when it is removed at the outset by genetic manipulation.
While it is possible that compensatory mechanisms develop in
IL-13-/- mice, the levels
of IL-4 in Ag-stimulated mice are unchanged from WT, at least in the
amount produced in the PBLN. Thus, although the genes encoding IL-4 and
IL-13 are proximal (34), it seems that the genomic
manipulation that created the
IL-13-/- mouse has not
induced covert perturbation in the expression of IL-4. However, the
significantly increased blood eosinophilia and AHR that develops in
IL-13-/- mice suggests
that some regulatory function may be compromised. Recently, IL-13 was
identified as a modulator of acute inflammatory responses by
suppressing the activation of NF-
B (35), a
transcription factor that is known to play a role in the expression of
IL-5, eotaxin, and eosinophilic inflammation in the lung in an
IL-4-independent manner (36). Therefore, it is possible
that the enhanced responses seen in
IL-13-/- mice may be
related to this IL-4-independent mechanism of eosinophilic inflammation
overlaid onto IL-4-dependent responses. Notionally, this is supported
by our observation that the levels of IL-5 and blood eosinophilia
produced in the absence of IL-4 are significantly greater in
IL-13-/- mice than in WT
mice. In addition, the controversy in the literature regarding the
requirement for IL-4 in the development of AHR may relate to the levels
of IL-13 induced in response to nuances in the sensitization regimes
employed in various models. It could be envisaged that low levels of
IL-13 may result in the activation of NF-B and an IL-4-independent
mechanism of IL-5 production and eosinophil mobilization. Conversely,
high levels of IL-13 may suppress this transcription factor and make
these processes more dependent on IL-4. This mechanism of
IL-4-independent inflammation may also be operative in nonallergic
asthmatics who have elevated levels of both IL-5 and eosinophils in the
absence of similarly elevated IL-4 (37).
Although it seems that an IL-4-independent process for the production of IL-5 occurs in IL-13-/- mice, this does not explain the observation that AHR in these mice is ablated by the neutralization of IL-4. In addition, our observation that eosinophilia and AHR develop in IL-13-/- mice contrasts with data from a previous study in which neutralization of IL-13 before aeroallergen challenge with a soluble form of the IL-13R ameliorated airway eosinophilia and AHR (24). This suggests that alternative mechanisms develop for the recruitment of eosinophils to the airways either when IL-13 is deficient at the outset as in IL-13-/- mice or when the level of IL-13 is modified by methodological variation in mouse models employed. Our data indicate that in fact a redundant IL-4 and IL-13 function underpins the migration of eosinophils into the pulmonary compartment in IL-13-/- mice. The absence of both cytokines severely impairs eosinophil migration into the tissues, and this probably relates to the important role these molecules play in stimulating the expression of adhesion molecules and chemokines, particularly eotaxin, within the lung (38, 39, 40, 41). These cytokines may also play a role in the activation of eosinophils, either directly or indirectly via the transmigratory process. Notably, while there is a certain redundancy in the function of these cytokines at the endothelial barrier, this is not the case at the airway epithelium in which IL-4 appears a more important regulator of the permeation of eosinophils into the airway lumen. Nonetheless, although a deficiency in IL-4 alone partially inhibited AHR, it was not sufficient to completely abrogate AHR in our model.
While the production of OVA-specific IgE was suppressed in IL-4-deficient mice, this did not occur in IL-13-/- mice, which produced levels of IgE that were similar to those produced in WT mice (data not shown). However, at this stage it is unknown what role IgE plays in the inflammatory responses that develop in IL-13-/- mice.
Although redundant signals elicited by either IL-4 or IL-13 appear to be required for the development of AHR, the role of eosinophils in this process is complex. Clearly, reduced numbers of tissue eosinophils in IL-13-/- mice, whether mediated by the reduced availability of blood eosinophils by the neutralization of IL-5 or by inhibiting the migration of eosinophils into the tissues by the neutralization of IL-4, correlate with a significant reduction in AHR. However, this is not the situation in WT mice in which a deficiency in IL-5 and a massively reduced tissue eosinophilia had little impact on AHR. These results are supported by our previous observations that identified a T cell-regulated mechanism in BALB/c mice that is independent of IL-4 and IL-5 for the induction of AHR (16). Probably two scenarios for the role of eosinophils in the development of AHR could be envisaged: either IL-13 is required to activate low levels of residual tissue eosinophils, or eosinophils provide an important AHR-associated factor that compensates for the deficiency in IL-13. The recent identification of eosinophils as a major source of IL-4 and IL-5 in schistosome granulomas (42, 43) as well as in asthmatics (36) may be particularly relevant to this issue. In the present study, neutralization of IL-5 in both WT and in IL-13-/- mice not only inhibited eosinophilia, but significantly inhibited the production of IL-4 by the PBLN. In contrast, neutralization of IL-5 had little effect on the PBLN secretion of IL-13. This suggests that eosinophils, either by direct secretion, or through a cooperativity with Ag-specific T cells may be an important source of IL-4, but not IL-13. Thus, neutralization of IL-5 in IL-13-/- mice may effectively dampen similar responses as occurs when IL-4 is deficient in these mice. Although the inhibition of IL-4 in WT mice reduced the levels of IL-13 produced by PBLN, significant levels of IL-13 persisted. Therefore, the redundancy in signals elicited by IL-4 and IL-13 may explain why the inhibition of IL-4 in WT mice in which IL-13 is plentiful fails to attenuate AHR. In addition, a deficiency of IL-5 in IL-13-/- mice, but not in WT mice, inhibited the production of IL-5 by PBLNs. This also suggests that eosinophils may be an important source of this cytokine in the absence of IL-13.
As the regional lymph nodes sample the microenvironment of the mucosa, they would be expected to reflect the cytokine production in the lung tissue. Recently, we have observed eosinophils in PBLN (44) and these leukocytes are known to act as APC (45, 46). Furthermore, the function of eosinophils as an important depot of cytokines would be expected to be enhanced in the bronchial mucosa in which these cells have a more predominant profile.
Recently, interest has focused on the role played by IL-4 or IL-13 in
the regulation of mucus production. Although IL-4 appears to modulate
the accumulation of mucus glycoprotein in the lung, signal transduction
via the IL-4R subunit is fundamental to this process (14, 47, 48, 49). In addition, neutralization of IL-13 with a soluble
rIL-13 receptor markedly inhibited both mucus hypersecretion and AHR in
response to aeroallergen challenge (26). In the present
study, specific histological staining showed that mucus hypersecretion
was dramatically reduced in sensitized
IL-13-/- mice compared
with both WT and IL-4-depleted mice. Significantly, the observation
that AHR persisted in these
IL-13-/- mice suggests
that the mechanism underlying the production of mucus and the presence
of secreted mucus in the airways are dissociated from the development
of AHR.
In conclusion, the functions of IL-13 in the development of AHR appear
to be temporal: a modulatory role during the sensitization process and
a proinflammatory role during challenge. The modulatory capacity of
IL-13 may relate to suppression of the activation of NF-B, and
concomitant IL-5 induced eosinophilic inflammation in an
IL-4-independent manner. In contrast, the proinflammatory role of IL-13
appears redundant with respect to IL-4. Either IL-4 or IL-13 can
instigate the transendothelial migration and probably activation of
eosinophils. These cells may then provide an important source of IL-4,
especially in situations in which IL-13 is deficient. Although the
cellular targets of these cytokines and the mechanisms associated with
AHR are yet to be clearly defined, the apparent redundancy in the
functions of IL-4 and IL-13 for the development of AHR suggests that
both cytokines, or their common receptor subunit IL-4R, may need to
be targeted for successful therapeutic intervention.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: AHR, airways hyperreactivity; PBLN, peribronchial lymph node; WT, wild type.
Received for publication January 21, 2000. Accepted for publication April 14, 2000.
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References |
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B in the induction of eosinophilia in allergic airway inflammation. J. Exp. Med. 188:1739., but not on eosinophils. J. Immunol. 162:6178.This article has been cited by other articles:
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A. Wittke, V. Weaver, B. D. Mahon, A. August, and M. T. Cantorna Vitamin D Receptor-Deficient Mice Fail to Develop Experimental Allergic Asthma J. Immunol., September 1, 2004; 173(5): 3432 - 3436. [Abstract] [Full Text] [PDF]
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 K. Clark, L. Simson, N. Newcombe, A. M. L. Koskinen, J. Mattes, N. A. Lee, J. J. Lee, L. A. Dent, K. I. Matthaei, and P. S. Foster Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen J. Leukoc. Biol., June 1, 2004; 75(6): 1001 - 1009. [Abstract] [Full Text] [PDF]
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S. Ishii, T. Nagase, H. Shindou, H. Takizawa, Y. Ouchi, and T. Shimizu Platelet-Activating Factor Receptor Develops Airway Hyperresponsiveness Independently of Airway Inflammation in a Murine Asthma Model J. Immunol., June 1, 2004; 172(11): 7095 - 7102. [Abstract] [Full Text] [PDF]
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R. Leigh, R. Ellis, J. N. Wattie, J. A. Hirota, K. I. Matthaei, P. S. Foster, P. M. O'Byrne, and M. D. Inman Type 2 Cytokines in the Pathogenesis of Sustained Airway Dysfunction and Airway Remodeling in Mice Am. J. Respir. Crit. Care Med., April 1, 2004; 169(7): 860 - 867. [Abstract] [Full Text] [PDF]
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M. Castro, S. R. Bloch, M. V. Jenkerson, S. DeMartino, D. L. Hamilos, R. B. Cochran, X. E. L. Zhang, H. Wang, J. P. Bradley, K. B. Schechtman, et al. Asthma Exacerbations after Glucocorticoid Withdrawal Reflects T Cell Recruitment to the Airway Am. J. Respir. Crit. Care Med., April 1, 2004; 169(7): 842 - 849. [Abstract] [Full Text] [PDF]
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N. Zimmermann, A. Mishra, N. E. King, P. C. Fulkerson, M. P. Doepker, N. M. Nikolaidis, L. E. Kindinger, E. A. Moulton, B. J. Aronow, and M. E. Rothenberg Transcript Signatures in Experimental Asthma: Identification of STAT6-Dependent and -Independent Pathways J. Immunol., February 1, 2004; 172(3): 1815 - 1824. [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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V. Smart, P. S. Foster, M. E. Rothenberg, T. J. V. Higgins, and S. P. Hogan A Plant-Based Allergy Vaccine Suppresses Experimental Asthma Via an IFN-{gamma} and CD4+CD45RBlow T Cell-Dependent Mechanism J. Immunol., August 15, 2003; 171(4): 2116 - 2126. [Abstract] [Full Text] [PDF]
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C. L. Hardy, L. Kenins, A. C. Drew, J. M. Rolland, and R. E. O'Hehir Characterization of a Mouse Model of Allergy to a Major Occupational Latex Glove Allergen Hev b 5 Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1393 - 1399. [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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J. Perez-Vilar, J. K. Sheehan, and S. H. Randell Making More MUCS Am. J. Respir. Cell Mol. Biol., March 1, 2003; 28(3): 267 - 270. [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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R. Leigh, R. Ellis, J. Wattie, D. S. Southam, M. de Hoogh, J. Gauldie, P. M. O'Byrne, and M. D. Inman Dysfunction and Remodeling of the Mouse Airway Persist after Resolution of Acute Allergen-Induced Airway Inflammation Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 526 - 535. [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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J. S. Welch, L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, and C. K. Glass TH2 Cytokines and Allergic Challenge Induce Ym1 Expression in Macrophages by a STAT6-dependent Mechanism J. Biol. Chem., November 1, 2002; 277(45): 42821 - 42829. [Abstract] [Full Text] [PDF]
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G. W. Wong, P. S. Foster, S. Yasuda, J. C. Qi, S. Mahalingam, E. A. Mellor, G. Katsoulotos, L. Li, J. A. Boyce, S. A. Krilis, et al. Biochemical and Functional Characterization of Human Transmembrane Tryptase (TMT)/Tryptase gamma . TMT IS AN EXOCYTOSED MAST CELL PROTEASE THAT INDUCES AIRWAY HYPERRESPONSIVENESS IN VIVO VIA AN INTERLEUKIN-13/INTERLEUKIN-4 RECEPTOR alpha /SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 6-DEPENDENT PATHWAY J. Biol. Chem., October 25, 2002; 277(44): 41906 - 41915. [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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R. K. Kumar and P. S. Foster Modeling Allergic Asthma in Mice: Pitfalls and Opportunities Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 267 - 272. [Abstract] [Full Text]
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K. A. Risma, N. Wang, R. P. Andrews, C. M. Cunningham, M. B. Ericksen, J. A. Bernstein, R. Chakraborty, and G. K. K. Hershey V75R576 IL-4 Receptor {alpha} Is Associated with Allergic Asthma and Enhanced IL-4 Receptor Function J. Immunol., August 1, 2002; 169(3): 1604 - 1610. [Abstract] [Full Text] [PDF]
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J. Mattes, M. Yang, S. Mahalingam, J. Kuehr, D. C. Webb, L. Simson, S. P. Hogan, A. Koskinen, A. N.J. McKenzie, L. A. Dent, et al. Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma J. Exp. Med., June 3, 2002; 195(11): 1433 - 1444. [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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M. M. Grunstein, H. Hakonarson, J. Leiter, M. Chen, R. Whelan, J. S. Grunstein, and S. Chuang IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle Am J Physiol Lung Cell Mol Physiol, March 1, 2002; 282(3): L520 - L528. [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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D. C. Webb, A. N. J. McKenzie, and P. S. Foster Expression of the Ym2 Lectin-binding Protein Is Dependent on Interleukin (IL)-4 and IL-13 Signal Transduction. IDENTIFICATION OF A NOVEL ALLERGY-ASSOCIATED PROTEIN J. Biol. Chem., November 2, 2001; 276(45): 41969 - 41976. [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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M. Hertz, S. Mahalingam, I. Dalum, S. Klysner, J. Mattes, A. Neisig, S. Mouritsen, P. S. Foster, and A. Gautam Active Vaccination Against IL-5 Bypasses Immunological Tolerance and Ameliorates Experimental Asthma J. Immunol., October 1, 2001; 167(7): 3792 - 3799. [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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J. G. Ford, D. Rennick, D. D. Donaldson, R. Venkayya, C. McArthur, E. Hansell, V. P. Kurup, M. Warnock, and G. Grunig IL-13 and IFN-{gamma}: Interactions in Lung Inflammation J. Immunol., August 1, 2001; 167(3): 1769 - 1777. [Abstract] [Full Text] [PDF]
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 J.C. Kips Cytokines in asthma Eur. Respir. J., July 2, 2001; 18(34_suppl): 24S - 33s. [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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K. Blease, C. Jakubzick, J. Westwick, N. Lukacs, S. L. Kunkel, and C. M. Hogaboam Therapeutic Effect of IL-13 Immunoneutralization During Chronic Experimental Fungal Asthma J. Immunol., April 15, 2001; 166(8): 5219 - 5224. [Abstract] [Full Text] [PDF]
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J.C. Kips, K.G. Tournoy, and R.A. Pauwels New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5 Eur. Respir. J., March 1, 2001; 17(3): 499 - 506. [Abstract] [Full Text] [PDF]
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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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