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Science 18 December 1998:
Vol. 282. no. 5397, pp. 2258 - 2261
DOI: 10.1126/science.282.5397.2258
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Reports

Interleukin-13: Central Mediator of Allergic Asthma

Marsha Wills-Karp, * Jackie Luyimbazi, Xueying Xu, Brian Schofield, Tamlyn Y. Neben, Christopher L. Karp, Debra D. Donaldson

The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4+ T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

M. Wills-Karp, J. Luyimbazi, X. Xu, B. Schofield, Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205, USA. T. Y. Neben and D. D. Donaldson, Immunology Department, Genetics Institute, Cambridge, MA 02140, USA. C. L. Karp, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, and Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205, USA.
*   To whom correspondence should be addressed. E-mail: mkarp{at}welchlink.welch.jhu.edu

Recent decades have brought dramatic increases in the prevalence and severity of allergic asthma. In the United States, 15 million people are currently thought to suffer from the disorder (1). Allergic asthma is characterized by airway hyperresponsiveness (AHR) to a variety of specific and nonspecific stimuli, chronic pulmonary eosinophilia, elevated serum immunoglobulin E (IgE), and excessive airway mucus production (2). The pathophysiology of asthma is thought to be mediated by CD4+ T lymphocytes producing a type 2 cytokine profile: (i) CD4+ T cells are necessary for the induction of allergic asthma in murine models; (ii) CD4+ T cells producing type 2 cytokines undergo expansion in these models and in patients with allergic asthma; and (iii) the amount of type 2 cytokines is increased in the airway tissues of asthmatics and animal models (3-5). The circumstantial evidence for the importance of IL-4 and IL-5, which are paradigmatic type 2 cytokines, has been compelling (6-8). However, although an antibody-mediated blockade of IL-4 during allergen sensitization ablates the development of allergic asthma, a similar blockade of IL-4 before or during an antigen challenge inhibits neither allergic inflammation nor AHR (9). Thus, IL-4 generates T helper cell 2 (TH2) deviation in these models (10) but is not necessary for the expression of allergic asthma. The CD4+ T cell-derived factor or factors that mediate allergic asthma remain elusive.

IL-13 is a TH2 cytokine that binds to the alpha  chain of the IL-4 receptor (11). We therefore examined the role of IL-13 in allergic asthma. A well-characterized murine model of allergic asthma was used, in which allergen exposure results in AHR, pulmonary eosinophilia, increases in antigen-specific serum IgE amounts, and increases in airway epithelial mucus content (12). Male A/J mice were immunized intraperitoneally and were subsequently challenged intratracheally with soluble ovalbumin (OVA); the allergic phenotype was assessed 4 days after the antigen challenge (13). Blockade of IL-13 was performed by the systemic administration of a soluble IL-13alpha 2-IgGFc fusion protein (sIL-13Ralpha 2-Fc), which specifically binds to and neutralizes IL-13, 24 hours before subsequent intratracheal allergen challenges (14). Antigen challenge of allergen-immunized mice resulted in significant increases in airway responsiveness to acetylcholine (15) (Fig. 1A). Blockade of IL-13 resulted in a complete reversal of such allergen-induced AHR; thus, IL-13 is necessary for the expression of AHR in this model. The ability of IL-13 ablation to reverse AHR after the full development of the phenotype of allergic asthma contrasts with the inability of IL-4 ablation to accomplish such a reversal. The mechanism underlying the effectiveness of IL-4Ralpha blockade in reversing allergen-induced AHR (12) may be the inhibition of IL-13-mediated processes, which is consistent with the fact that Stat6 activation is downstream of IL-4Ralpha -mediated signaling for both cytokines. IL-13 is probably the primary CD4+ T cell-derived factor responsible for allergen-induced AHR.

Fig. 1. Reversal of allergen-induced AHR by the in vivo blockade of IL-13. Ten days after the initial intratracheal challenge, OVA- and PBS-immunized mice were again challenged intratracheally with either OVA or PBS. Mice were given sIL-13Ralpha 2-Fc (400 µg) or an equivalent amount of control human Ig (Hu-Ig) by intraperitoneal injection on days -1, 0, +1, and +3 of the secondary antigen challenge. The allergic phenotype was assessed 4 days after the PBS or OVA challenge. (A) AHR to the acetylcholine challenge, defined by the time-integrated rise in peak airway pressure [airway-pressure-time index (APTI) in centimeters of H2O × seconds]. (B) Inflammatory cell composition of BAL fluids. Cell differential percentages were determined by light microscopic evaluation of cytospin preparations. Data are expressed as absolute numbers of cells. (C) OVA-specific serum IgE concentrations. In (A) through (C), the results are means ± SEM (error bars) of 8 to 10 animals per group and are representative of two independent experiments. *P < 0.05, compared with the respective PBS control groups; **P < 0.05, compared to the OVA+Hu-Ig group [one-way analysis of variance (ANOVA) followed by Fisher's least significant difference test for multiple comparisons]. [View Larger Version of this Image (19K GIF file)]

To evaluate the candidate mechanisms underlying IL-13-dependent expression of AHR, we characterized known allergic effector cascades. Eosinophils have been implicated as primary effector cells in asthma and asthmatic AHR (16), but the inhibition of IL-13 before repeat antigen provocation did not significantly affect allergen-induced pulmonary eosinophilia (17) (Fig. 1B). To assess the relevance of IgE-mediated pathways, we measured OVA-specific serum IgE (18). OVA-specific IgE was observed in OVA-sensitized and OVA-challenged mice, whereas no antigen-specific antibody was detected in phosphate-buffered saline (PBS)-immunized and PBS-challenged mice (Fig. 1C). Blockade of IL-13 did not alter OVA-specific IgE concentrations--a lack of suppression that is likely due to the fact that the IL-13 blockade occurred after initial antigen priming and antibody formation. Nonetheless, these results show that AHR is not dependent on IgE production in this model, which is consistent with a report that allergic AHR develops normally in IgE-deficient mice (19).

In congruence with the pathology of human asthma, allergic asthma in murine models is associated with a substantial increase in the mucus content of the airway epithelium (7, 12). Mucus hypersecretion is particularly profound in autopsy specimens from patients who die of acute asthma attacks (20). Blockade of IL-13 reverses allergen-induced increases in mucus-containing cells in the airways (Fig. 2), demonstrating that allergen-induced increases in airway mucus content are dependent on IL-13. IL-4 has also been implicated in this process, because IL-4 transgenic mice display goblet-cell hyperplasia in the absence of antigen sensitization (7). However, the transfer of TH2 clones from IL-4-deficient mice into murine airways induces mucus overproduction (21), which suggests that the immunoregulatory role of IL-4 should be carefully differentiated from its role as an effector molecule.

Fig. 2. Effects of the IL-13 blockade on allergen-driven increases in mucus-containing cells in the airway epithelium. Lung sections (four per experimental group and four sections per animal) were fixed in formalin; cut into 10-µm sections; and stained with hematoxylin, eosin, and periodic acid-Schiff. Representative sections are shown. (A) PBS+Hu-Ig section showing PBS-immunized and PBS-challenged controls and few mucus-containing cells. (B) OVA+Hu-Ig section showing allergen-induced increases in interstitial inflammatory cells and increases in the number of goblet cells containing mucus. (C) OVA+sIL-13Ralpha 2-Fc section showing the inhibitory effect of the IL-13 blockade on allergen-induced mucus production in goblet cells. These data are representative of two independent experiments. [View Larger Version of this Image (55K GIF file)]

If IL-13 is necessary for the expression of allergic AHR, is it sufficient to induce it? The daily administration of recombinant IL-13 (rIL-13) to the airways of naïve (unimmunized) mice induced AHR, demonstrating that increases in IL-13 activity were sufficient to induce AHR (Fig. 3A) (22). AHR developed within 72 hours from the start of rIL-13 administration. A significant influx of eosinophils into bronchoalveolar lavage (BAL) fluid was observed soon after rIL-13 administration; however, pulmonary eosinophilia was not observed at the time of expression of AHR (Fig. 3B). Although the importance of the time course of eosinophil influx remains unclear, it suggests that IL-13 alone may be sufficient to initiate eosinophilic infiltration of the airways, perhaps through its ability to up-regulate chemokine expression (23). Airway administration of rIL-13 also resulted in a time-dependent increase in total serum IgE (Fig. 3C) (24), which is in line with the ability of IL-13 to regulate IgE synthesis (25). Increases in serum IgE were independent of any immunization with allergen; these findings are consistent with the observation that the human asthmatic phenotype correlates better with total, rather than allergen-specific, serum IgE concentrations (26). As predicted from our IL-13 inhibition studies, the administration of rIL-13 induced an increase in airway mucus production (Fig. 3D) (27).

Fig. 3. IL-13 induction of airway hyperreactivity. Naïve mice were given murine rIL-13 (5 µg per mouse in a total volume of 50 µl) or PBS daily by intratracheal instillation. Twenty-four and 72 hours after the last treatment, (A) AHR, (B) BAL eosinophil numbers, and (C) serum total IgE concentrations were determined; (D) the mucus score was determined 72 hours after treatment. In (A) through (D), the results are means ± SEM (error bars) of 7 to 10 animals per group and are representative of three independent experiments. *P < 0.05, compared to the PBS group (Student's t test). [View Larger Version of this Image (26K GIF file)]

Although IL-13 thus appears capable of inducing the entire allergic asthmatic phenotype, the results of the IL-13 blockade experiments clearly show that IL-13-dependent AHR occurs by mechanisms that are independent of IgE and eosinophils in this model. The exact mechanism or mechanisms by which IL-13 induces AHR are currently unknown. The delayed time course for AHR induction suggests that IL-13 does not directly cause airway smooth muscle constriction. Reasonable hypotheses include direct time-dependent alterations in smooth muscle function (IL-13 receptors have yet to be demonstrated on airway smooth muscle) and indirect effects that are achieved through mediators released by surrounding cells. Although recent studies have suggested a possible role for sensory neuron-derived tachykinins in AHR, preliminary studies in our laboratory do not support a role for these neuropeptides in IL-13-induced AHR (28).

Our data demonstrate a critical role for IL-13 in the expression of murine asthma and suggest that, although IL-4 may be of immunoregulatory importance, IL-4 is not a prime effector molecule. These findings may be relevant to human asthma. Overexpression of IL-4 is predominantly found in the airways of allergic asthmatics, whereas significant elevations in IL-13 expression are found in the airways of patients with both allergic and nonallergic asthma (4, 29). Human asthma has been linked to a region of chromosome 5q, which contains the genes for both IL-4 and IL-13 (30). Although polymorphisms in the IL-13 gene have yet to be examined, polymorphisms in the IL-4 gene are well-described (31). No significant correlations between such polymorphisms and the asthmatic phenotype have been found; however, a gain-of-function mutation in IL-4Ralpha was recently shown to be associated with asthma (32). These insights into the immunopathogenesis of allergic asthma should provide direction for the development of therapeutics for this increasingly prevalent disease.

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4 September 1998; accepted 6 November 1998


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   Abstract »    Full Text »    PDF »
Eosinophilic and Neutrophilic Inflammation in Asthma: Insights from Clinical Studies.
J. V. Fahy (2009)
Proceedings of the ATS 6, 256-259
   Abstract »    Full Text »    PDF »
A Functional IL-13 Receptor Is Expressed on Polarized Murine CD4+ Th17 Cells and IL-13 Signaling Attenuates Th17 Cytokine Production.
D. C. Newcomb, W. Zhou, M. L. Moore, K. Goleniewska, G. K. K. Hershey, J. K. Kolls, and R. S. Peebles Jr. (2009)
J. Immunol. 182, 5317-5321
   Abstract »    Full Text »    PDF »
Resolution of Allergic Inflammation and Airway Hyperreactivity Is Dependent upon Disruption of the T1/ST2-IL-33 Pathway.
J. Kearley, K. F. Buckland, S. A. Mathie, and C. M. Lloyd (2009)
Am. J. Respir. Crit. Care Med. 179, 772-781
   Abstract »    Full Text »    PDF »
Th2 cytokine-induced upregulation of 11{beta}-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function.
A. Hu, S. Fatma, J. Cao, J. S. Grunstein, G. Nino, Y. Grumbach, and M. M. Grunstein (2009)
Am J Physiol Lung Cell Mol Physiol 296, L790-L803
   Abstract »    Full Text »    PDF »
Induction of Airway Hyperreactivity by IL-25 Is Dependent on a Subset of Invariant NKT Cells Expressing IL-17RB.
P. Stock, V. Lombardi, V. Kohlrautz, and O. Akbari (2009)
J. Immunol. 182, 5116-5122
   Abstract »    Full Text »    PDF »
A Protective Role for C5a in the Development of Allergic Asthma Associated with Altered Levels of B7-H1 and B7-DC on Plasmacytoid Dendritic Cells.
X. Zhang, I. P. Lewkowich, G. Kohl, J. R. Clark, M. Wills-Karp, and J. Kohl (2009)
J. Immunol. 182, 5123-5130
   Abstract »    Full Text »    PDF »
Inhaled Multiwalled Carbon Nanotubes Potentiate Airway Fibrosis in Murine Allergic Asthma.
J. P. Ryman-Rasmussen, E. W. Tewksbury, O. R. Moss, M. F. Cesta, B. A. Wong, and J. C. Bonner (2009)
Am. J. Respir. Cell Mol. Biol. 40, 349-358
   Abstract »    Full Text »    PDF »
Mucins, Mucus, and Sputum.
J. A. Voynow and B. K. Rubin (2009)
Chest 135, 505-512
   Abstract »    Full Text »    PDF »
Interleukin-13 Augments Bronchial Smooth Muscle Contractility with an Up-Regulation of RhoA Protein.
Y. Chiba, S. Nakazawa, M. Todoroki, K. Shinozaki, H. Sakai, and M. Misawa (2009)
Am. J. Respir. Cell Mol. Biol. 40, 159-167
   Abstract »    Full Text »    PDF »
Acute Exercise Decreases Airway Inflammation, but Not Responsiveness, in an Allergic Asthma Model.
M. Hewitt, A. Creel, K. Estell, I. C. Davis, and L. M. Schwiebert (2009)
Am. J. Respir. Cell Mol. Biol. 40, 83-89
   Abstract »    Full Text »    PDF »
The extracellular matrix protein mindin regulates trafficking of murine eosinophils into the airspace.
Z. Li, S. Garantziotis, W. Jia, E. N. Potts, S. Lalani, Z. Liu, Y.-W. He, W. M. Foster, and J. W. Hollingsworth (2009)
J. Leukoc. Biol. 85, 124-131
   Abstract »    Full Text »    PDF »
CD11b+ Myeloid Cells Are the Key Mediators of Th2 Cell Homing into the Airway in Allergic Inflammation.
B. D. Medoff, E. Seung, S. Hong, S. Y. Thomas, B. P. Sandall, J. S. Duffield, D. A. Kuperman, D. J. Erle, and A. D. Luster (2009)
J. Immunol. 182, 623-635
   Abstract »    Full Text »    PDF »
Untangling the Complex Web of IL-4- and IL-13-Mediated Signaling Pathways.
M. Wills-Karp and F. D. Finkelman (2008)
Science Signaling 1, pe55
   Abstract »    Full Text »    PDF »
Type I IL-4Rs Selectively Activate IRS-2 to Induce Target Gene Expression in Macrophages.
N. M. Heller, X. Qi, I. S. Junttila, K. A. Shirey, S. N. Vogel, W. E. Paul, and A. D. Keegan (2008)
Science Signaling 1, ra17
   Abstract »    Full Text »    PDF »
Mice Lacking 12/15-Lipoxygenase Have Attenuated Airway Allergic Inflammation and Remodeling.
C. K. Andersson, H.-E. Claesson, K. Rydell-Tormanen, S. Swedmark, A. Hallgren, and J. S. Erjefalt (2008)
Am. J. Respir. Cell Mol. Biol. 39, 648-656
   Abstract »    Full Text »    PDF »
A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity.
A. Terashima, H. Watarai, S. Inoue, E. Sekine, R. Nakagawa, K. Hase, C. Iwamura, H. Nakajima, T. Nakayama, and M. Taniguchi (2008)
J. Exp. Med. 205, 2727-2733
   Abstract »    Full Text »    PDF »
Selective Expression Rather than Specific Function of Txk and Itk Regulate Th1 and Th2 Responses.
N. Sahu, A. M. Venegas, D. Jankovic, W. Mitzner, J. Gomez-Rodriguez, J. L. Cannons, C. Sommers, P. Love, A. Sher, P. L. Schwartzberg, et al. (2008)
J. Immunol. 181, 6125-6131
   Abstract »    Full Text »    PDF »
Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4R{alpha}, IL-13R{alpha}1, and {gamma}c regulates relative cytokine sensitivity.
I. S. Junttila, K. Mizukami, H. Dickensheets, M. Meier-Schellersheim, H. Yamane, R. P. Donnelly, and W. E. Paul (2008)
J. Exp. Med. 205, 2595-2608
   Abstract »    Full Text »    PDF »
IL-33 Induces Antigen-Specific IL-5+ T Cells and Promotes Allergic-Induced Airway Inflammation Independent of IL-4.
M. Kurowska-Stolarska, P. Kewin, G. Murphy, R. C. Russo, B. Stolarski, C. C. Garcia, M. Komai-Koma, N. Pitman, Y. Li, A. N. J. McKenzie, et al. (2008)
J. Immunol. 181, 4780-4790
   Abstract »    Full Text »    PDF »
B7-H3 Contributes to the Development of Pathogenic Th2 Cells in a Murine Model of Asthma.
O. Nagashima, N. Harada, Y. Usui, T. Yamazaki, H. Yagita, K. Okumura, K. Takahashi, and H. Akiba (2008)
J. Immunol. 181, 4062-4071
   Abstract »    Full Text »    PDF »
Preclinical Safety and Pharmacology of an Anti-Human Interleukin-13 Monoclonal Antibody in Normal Macaques and in Macaques with Allergic Asthma.
P. L. Martin, D. Fisher, W. Glass, K. O'Neil, A. Das, E. C. Martin, and L. Li (2008)
International Journal of Toxicology 27, 351-358
   Abstract »    Full Text »    PDF »
Pivotal Advance: IgE accelerates in vitro development of mast cells and modifies their phenotype.
J.-i. Kashiwakura, W. Xiao, J. Kitaura, Y. Kawakami, M. Maeda-Yamamoto, J. R. Pfeiffer, B. S. Wilson, U. Blank, and T. Kawakami (2008)
J. Leukoc. Biol. 84, 357-367
   Abstract »    Full Text »    PDF »
Adenovirus IL-13-Induced Airway Disease in Mice: A Corticosteroid-Resistant Model of Severe Asthma.
A. G. Therien, V. Bernier, S. Weicker, P. Tawa, J.-P. Falgueyret, M.-C. Mathieu, J. Honsberger, V. Pomerleau, A. Robichaud, R. Stocco, et al. (2008)
Am. J. Respir. Cell Mol. Biol. 39, 26-35
   Abstract »    Full Text »    PDF »
MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells.
B. Moynihan, B. Tolloczko, M.-C. Michoud, M. Tamaoka, P. Ferraro, and J. G. Martin (2008)
Am J Physiol Lung Cell Mol Physiol 295, L171-L177
   Abstract »    Full Text »    PDF »
Interleukin-4 activates large-conductance, calcium-activated potassium (BKCa) channels in human airway smooth muscle cells.
G. Martin, R. J. O'Connell, A. Z. Pietrzykowski, S. N. Treistman, M. F. Ethier, and J. M. Madison (2008)
Exp Physiol 93, 908-918
   Abstract »    Full Text »    PDF »
A dual activation and inhibition role for the paired immunoglobulin-like receptor B in eosinophils.
A. Munitz, M. L. McBride, J. S. Bernstein, and M. E. Rothenberg (2008)
Blood 111, 5694-5703
   Abstract »    Full Text »    PDF »
Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma.
E. R. Walsh, N. Sahu, J. Kearley, E. Benjamin, B. H. Kang, A. Humbles, and A. August (2008)
J. Exp. Med. 205, 1285-1292
   Abstract »    Full Text »    PDF »
Nicotine Primarily Suppresses Lung Th2 but Not Goblet Cell and Muscle Cell Responses to Allergens.
N. C. Mishra, J. Rir-sima-ah, R. J. Langley, S. P. Singh, J. C. Pena-Philippides, T. Koga, S. Razani-Boroujerdi, J. Hutt, M. Campen, K. C. Kim, et al. (2008)
J. Immunol. 180, 7655-7663
   Abstract »    Full Text »    PDF »
Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation.
M. Okamoto, K. Takeda, A. Joetham, H. Ohnishi, H. Matsuda, C. H. Swasey, B. J. Swanson, K. Yasutomo, A. Dakhama, and E. W. Gelfand (2008)
J. Exp. Med. 205, 1087-1097
   Abstract »    Full Text »    PDF »
Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease.
I. Nakao, S. Kanaji, S. Ohta, H. Matsushita, K. Arima, N. Yuyama, M. Yamaya, K. Nakayama, H. Kubo, M. Watanabe, et al. (2008)
J. Immunol. 180, 6262-6269
   Abstract »    Full Text »    PDF »
Induction of Adaptive T Regulatory Cells That Suppress the Allergic Response by Coimmunization of DNA and Protein Vaccines.
H. Jin, Y. Kang, L. Zhao, C. Xiao, Y. Hu, R. She, Y. Yu, X. Du, G. Zhao, T. Ng, et al. (2008)
J. Immunol. 180, 5360-5372
   Abstract »    Full Text »    PDF »
ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival.
O. Akbari, P. Stock, E. H. Meyer, G. J. Freeman, A. H. Sharpe, D. T. Umetsu, and R. H. DeKruyff (2008)
J. Immunol. 180, 5448-5456
   Abstract »    Full Text »    PDF »
Mast cell-derived tumour necrosis factor is essential for allergic airway disease.
S. Reuter, A. Heinz, M. Sieren, R. Wiewrodt, E. W. Gelfand, M. Stassen, R. Buhl, and C. Taube (2008)
Eur. Respir. J. 31, 773-782
   Abstract »    Full Text »    PDF »
Development of Chronic Bronchitis and Emphysema in {beta}-Epithelial Na+ Channel-Overexpressing Mice.
M. A. Mall, J. R. Harkema, J. B. Trojanek, D. Treis, A. Livraghi, S. Schubert, Z. Zhou, S. M. Kreda, S. L. Tilley, E. J. Hudson, et al. (2008)
Am. J. Respir. Crit. Care Med. 177, 730-742
   Abstract »    Full Text »    PDF »
Effects of allergen on airway narrowing dynamics as assessed by lung-slice technique.
A. D. Chew, J. A. Hirota, R. Ellis, J. Wattie, M. D. Inman, and L. J. Janssen (2008)
Eur. Respir. J. 31, 532-538
   Abstract »    Full Text »    PDF »
IL-9 and IL-13 Induce Mucous Cell Metaplasia That Is Reduced by IFN-{gamma} in a Bax-Mediated Pathway.
J. Xiang, J. Rir-Sim-Ah, and Y. Tesfaigzi (2008)
Am. J. Respir. Cell Mol. Biol. 38, 310-317
   Abstract »    Full Text »    PDF »
IL-4 Is a Critical Determinant in the Generation of Allergic Inflammation Initiated by a Constitutively Active Stat6.
S. Sehra, H. A. Bruns, A.-N. N. Ahyi, E. T. Nguyen, N. W. Schmidt, E. G. Michels, G.-U. von Bulow, and M. H. Kaplan (2008)
J. Immunol. 180, 3551-3559
   Abstract »    Full Text »    PDF »
Murine Cytomegalovirus Influences Foxj1 Expression, Ciliogenesis, and Mucus Plugging in Mice with Allergic Airway Disease.
C. A. Wu, J. J. Peluso, J. D. Shanley, L. Puddington, and R. S. Thrall (2008)
Am. J. Pathol. 172, 714-724
   Abstract »    Full Text »    PDF »
Pulmonary arterial remodeling induced by a Th2 immune response.
E. Daley, C. Emson, C. Guignabert, R. de Waal Malefyt, J. Louten, V. P. Kurup, C. Hogaboam, L. Taraseviciene-Stewart, N. F. Voelkel, M. Rabinovitch, et al. (2008)
J. Exp. Med. 205, 361-372
   Abstract »    Full Text »    PDF »
Chlamydia muridarum Infection Subverts Dendritic Cell Function to Promote Th2 Immunity and Airways Hyperreactivity.
G. E. Kaiko, S. Phipps, D. K. Hickey, C. E. Lam, P. M. Hansbro, P. S. Foster, and K. W. Beagley (2008)
J. Immunol. 180, 2225-2232
   Abstract »    Full Text »    PDF »
Secretion of IL-13 by Airway Epithelial Cells Enhances Epithelial Repair via HB-EGF.
S. Allahverdian, N. Harada, G. K. Singhera, D. A. Knight, and D. R. Dorscheid (2008)
Am. J. Respir. Cell Mol. Biol. 38, 153-160
   Abstract »    Full Text »    PDF »
Role of CD38 in TNF-{alpha}-induced airway hyperresponsiveness.
A. G. P. Guedes, J. A. Jude, J. Paulin, H. Kita, F. E. Lund, and M. S. Kannan (2008)
Am J Physiol Lung Cell Mol Physiol 294, L290-L299
   Abstract »    Full Text »    PDF »
Calcium Signaling in Airway Smooth Muscle.
J. A. Jude, M. E. Wylam, T. F. Walseth, and M. S. Kannan (2008)
Proceedings of the ATS 5, 15-22
   Abstract »    Full Text »    PDF »
Gene Expression in Asthmatic Airway Smooth Muscle.
P. G. Woodruff (2008)
Proceedings of the ATS 5, 113-118
   Abstract »    Full Text »    PDF »
IL-13 Receptor {alpha}2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung.
T. Zheng, W. Liu, S.-Y. Oh, Z. Zhu, B. Hu, R. J. Homer, L. Cohn, M. J. Grusby, and J. A. Elias (2008)
J. Immunol. 180, 522-529
   Abstract »    Full Text »    PDF »
Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses.
X. Zhao, B. Zheng, Y. Huang, D. Yang, S. Katzman, C. Chang, D. Fowell, and W.-p. Zeng (2007)
J. Immunol. 179, 8297-8304
   Abstract »    Full Text »    PDF »
Differences in Expression, Affinity, and Function of Soluble (s)IL-4R{alpha} and sIL-13R{alpha}2 Suggest Opposite Effects on Allergic Responses.
M. Khodoun, C. Lewis, J.-Q. Yang, T. Orekov, C. Potter, T. Wynn, M. Mentink-Kane, G. K. Khurana Hershey, M. Wills-Karp, and F. D. Finkelman (2007)
J. Immunol. 179, 6429-6438
   Abstract »    Full Text »    PDF »
Anti-inflammatory and Immune-regulatory Effects of Subcutaneous Perillae Fructus Extract Injections on OVA-induced Asthma in Mice.
Y.-K. Yim, H. Lee, K.-E. Hong, Y.-I. Kim, S.-K. Ko, J.-E. Kim, S.-Y. Lee, and K.-S. Park (2007)
Evid. Based Complement. Altern. Med.
   Abstract »    Full Text »    PDF »
An International Case-Control Study of Interleukin-4R{alpha}, Interleukin-13, and Cyclooxygenase-2 Polymorphisms and Glioblastoma Risk.
J. A. Schwartzbaum, A. Ahlbom, S. Lonn, B. Malmer, A. Wigertz, A. Auvinen, A. J. Brookes, H. Collatz Christensen, R. Henriksson, C. Johansen, et al. (2007)
Cancer Epidemiol. Biomarkers Prev. 16, 2448-2454
   Abstract »    Full Text »    PDF »
Th2 Cytokines in Skin Draining Lymph Nodes and Serum IgE Do Not Predict Airway Hypersensitivity to Intranasal Isocyanate Exposure in Mice.
A. K. Farraj, E. Boykin, N. Haykal-Coates, S. H. Gavett, D. Doerfler, and M. Selgrade (2007)
Toxicol. Sci. 100, 99-108
   Abstract »    Full Text »    PDF »
The Immunopathogenesis of Chronic Obstructive Pulmonary Disease: Insights from Recent Research.
J. L. Curtis, C. M. Freeman, and J. C. Hogg (2007)
Proceedings of the ATS 4, 512-521
   Abstract »    Full Text »    PDF »
Allergic Airway Responses in Obese Mice.
R. A. Johnston, M. Zhu, Y. M. Rivera-Sanchez, F. L. Lu, T. A. Theman, L. Flynt, and S. A. Shore (2007)
Am. J. Respir. Crit. Care Med. 176, 650-658
   Abstract »    Full Text »    PDF »
Neonatal Chlamydial Infection Induces Mixed T-Cell Responses That Drive Allergic Airway Disease.
J. C. Horvat, K. W. Beagley, M. A. Wade, J. A. Preston, N. G. Hansbro, D. K. Hickey, G. E. Kaiko, P. G. Gibson, P. S. Foster, and P. M. Hansbro (2007)
Am. J. Respir. Crit. Care Med. 176, 556-564
   Abstract »    Full Text »    PDF »
T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-{gamma} and IL-13 production.
N. Hayashi, T. Yoshimoto, K. Izuhara, K. Matsui, T. Tanaka, and K. Nakanishi (2007)
PNAS 104, 14765-14770
   Abstract »    Full Text »    PDF »
Central Role of Muc5ac Expression in Mucous Metaplasia and Its Regulation by Conserved 5' Elements.
H. W. J. Young, O. W. Williams, D. Chandra, L. K. Bellinghausen, G. Perez, A. Suarez, M. J. Tuvim, M. G. Roy, S. N. Alexander, S. J. Moghaddam, et al. (2007)
Am. J. Respir. Cell Mol. Biol. 37, 273-290
   Abstract »    Full Text »    PDF »
Novel Recombinant Interleukin-13 Peptide-based Vaccine Reduces Airway Allergic Inflammatory Responses in Mice.
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 (2007)
Am. J. Respir. Crit. Care Med. 176, 439-445
   Abstract »    Full Text »    PDF »
Inhibition of Experimental Allergic Airways Disease by Local Application of a Cell-Penetrating Dominant-Negative STAT-6 Peptide.
C. T. McCusker, Y. Wang, J. Shan, M. W. Kinyanjui, A. Villeneuve, H. Michael, and E. D. Fixman (2007)
J. Immunol. 179, 2556-2564
   Abstract »    Full Text »    PDF »
Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung.
A. Mishra, M. Wang, J. Schlotman, N. M. Nikolaidis, C. W. DeBrosse, M. L. Karow, and M. E. Rothenberg (2007)
Am J Physiol Lung Cell Mol Physiol 293, L305-L313
   Abstract »    Full Text »    PDF »
Measurement of IL-13-Induced iNOS-Derived Gas Phase Nitric Oxide in Human Bronchial Epithelial Cells.
V. Suresh, J. D. Mih, and S. C. George (2007)
Am. J. Respir. Cell Mol. Biol. 37, 97-104
   Abstract »    Full Text »    PDF »
Galectin-9 Inhibits CD44-Hyaluronan Interaction and Suppresses a Murine Model of Allergic Asthma.
S. Katoh, N. Ishii, A. Nobumoto, K. Takeshita, S.-Y. Dai, R. Shinonaga, T. Niki, N. Nishi, A. Tominaga, A. Yamauchi, et al. (2007)
Am. J. Respir. Crit. Care Med. 176, 27-35
   Abstract »    Full Text »    PDF »
T-cell co-stimulatory molecules: their role in allergic immune reactions.
T. Kallinich, K. C. Beier, U. Wahn, P. Stock, and E. Hamelmann (2007)
Eur. Respir. J. 29, 1246-1255
   Abstract »    Full Text »    PDF »
4-1BB triggers IL-13 production from T cells to limit the polarized, Th1-mediated inflammation.
S. M. Shin, Y. H. Kim, B. K. Choi, P. M. Kwon, H.-W. Lee, and B. S. Kwon (2007)
J. Leukoc. Biol. 81, 1455-1465
   Abstract »    Full Text »    PDF »
Lack of lymphoid chemokines CCL19 and CCL21 enhances allergic airway inflammation in mice.
B. Xu, K. Aoyama, M. Kusumoto, A. Matsuzawa, E. C. Butcher, S. A. Michie, T. Matsuyama, and T. Takeuchi (2007)
Int. Immunol. 19, 775-784
   Abstract »    Full Text »    PDF »
Comparison of Airway Remodeling in Acute, Subacute, and Chronic Models of Allergic Airways Disease.
N. R. Locke, S. G. Royce, J. S. Wainewright, C. S. Samuel, and M. L. Tang (2007)
Am. J. Respir. Cell Mol. Biol. 36, 625-632
   Abstract »    Full Text »    PDF »
Remodeling and Airway Hyperresponsiveness but Not Cellular Inflammation Persist after Allergen Challenge in Asthma.
H. H. Kariyawasam, M. Aizen, J. Barkans, D. S. Robinson, and A. B. Kay (2007)
Am. J. Respir. Crit. Care Med. 175, 896-904
   Abstract »    Full Text »    PDF »
A deficient TLR2 signaling promotes airway mucin production in Mycoplasma pneumoniae-infected allergic mice.
Q. Wu, R. J. Martin, J. G. Rino, S. Jeyaseelan, R. Breed, and H. W. Chu (2007)
Am J Physiol Lung Cell Mol Physiol 292, L1064-L1072
   Abstract »    Full Text »    PDF »
Airway Exposure Levels of Lipopolysaccharide Determine Type 1 versus Type 2 Experimental Asthma.
Y.-K. Kim, S.-Y. Oh, S. G. Jeon, H.-W. Park, S.-Y. Lee, E.-Y. Chun, B. Bang, H.-S. Lee, M.-H. Oh, Y.-S. Kim, et al. (2007)
J. Immunol. 178, 5375-5382
   Abstract »    Full Text »    PDF »
Lysophosphatidic Acid Induces Interleukin-13 (IL-13) Receptor {alpha}2 Expression and Inhibits IL-13 Signaling in Primary Human Bronchial Epithelial Cells.
Y. Zhao, D. He, J. Zhao, L. Wang, A. R. Leff, E. Wm. Spannhake, S. Georas, and V. Natarajan (2007)
J. Biol. Chem. 282, 10172-10179
   Abstract »    Full Text »    PDF »
Superantigen Presentation by Airway Smooth Muscle to CD4+ T Lymphocytes Elicits Reciprocal Proasthmatic Changes in Airway Function.
H. Veler, A. Hu, S. Fatma, J. S. Grunstein, C. M. DeStephan, D. Campbell, J. S. Orange, and M. M. Grunstein (2007)
J. Immunol. 178, 3627-3636
   Abstract »    Full Text »    PDF »
Posttranscriptional Inhibition of Interferon-Gamma Production by Lead.
Y. Heo, T. K. Mondal, D. Gao, J. Kasten-Jolly, H. Kishikawa, and D. A. Lawrence (2007)
Toxicol. Sci. 96, 92-100
   Abstract »    Full Text »    PDF »
Efficacy of IL-13 Neutralization in a Sheep Model of Experimental Asthma.
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. (2007)
Am. J. Respir. Cell Mol. Biol. 36, 368-376
   Abstract »    Full Text »    PDF »
IL-2 and IL-18 Attenuation of Airway Hyperresponsiveness Requires STAT4, IFN-{gamma}, and Natural Killer Cells.
S. Matsubara, K. Takeda, T. Kodama, A. Joetham, N. Miyahara, T. Koya, C. H. Swasey, M. Okamoto, A. Dakhama, and E. W. Gelfand (2007)
Am. J. Respir. Cell Mol. Biol. 36, 324-332
   Abstract »    Full Text »    PDF »
IL-13 Mediates In Vivo IL-9 Activities on Lung Epithelial Cells but Not on Hematopoietic Cells.
V. Steenwinckel, J. Louahed, C. Orabona, F. Huaux, G. Warnier, A. McKenzie, D. Lison, R. Levitt, and J.-C. Renauld (2007)
J. Immunol. 178, 3244-3251
   Abstract »    Full Text »    PDF »
Functional Dissection Identifies a Conserved Noncoding Sequence-1 Core That Mediates IL13 and IL4 Transcriptional Enhancement.
J. M. Strempel and D. Vercelli (2007)
J. Biol. Chem. 282, 3738-3746
   Abstract »    Full Text »    PDF »
IL-13 and Epidermal Growth Factor Receptor Have Critical but Distinct Roles in Epithelial Cell Mucin Production.
G. Zhen, S. W. Park, L. T. Nguyenvu, M. W. Rodriguez, R. Barbeau, A. C. Paquet, and D. J. Erle (2007)
Am. J. Respir. Cell Mol. Biol. 36, 244-253
   Abstract »    Full Text »    PDF »


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