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• W1979732414 abstract "Decades of research in animal models have provided abundant evidence to show that IL-13 is a key TH2 cytokine that directs many of the important features of airway inflammation and remodeling in patients with allergic asthma. Several promising focused therapies for asthma that target the IL-13/IL-4/signal transducer and activator of transcription 6 pathway are in development, including anti–IL-13 mAbs and IL-4 receptor antagonists. The efficacy of these new potential asthma therapies depends on the responsiveness of patients. However, an understanding of how IL-13–directed therapies might benefit asthmatic patients is confounded by the complex heterogeneity of the disease. Recent efforts to classify subphenotypes of asthma have focused on sputum cellular inflammation profiles, as well as cluster analyses of clinical variables and molecular and genetic signatures. Researchers and clinicians can now evaluate biomarkers of TH2-driven airway inflammation in asthmatic patients, such as serum IgE levels, sputum eosinophil counts, fraction of exhaled nitric oxide levels, and serum periostin levels, to aid decision making in clinical trials and drug development and to identify subsets of patients who might benefit from therapies. Although it is unlikely that these therapies will benefit all asthmatic patients with this heterogeneous disease, advances in understanding asthma subphenotypes in relation to clinical variables and TH2 cytokine responses offer the opportunity to improve the efficacy and safety of proposed therapies for asthma. Decades of research in animal models have provided abundant evidence to show that IL-13 is a key TH2 cytokine that directs many of the important features of airway inflammation and remodeling in patients with allergic asthma. Several promising focused therapies for asthma that target the IL-13/IL-4/signal transducer and activator of transcription 6 pathway are in development, including anti–IL-13 mAbs and IL-4 receptor antagonists. The efficacy of these new potential asthma therapies depends on the responsiveness of patients. However, an understanding of how IL-13–directed therapies might benefit asthmatic patients is confounded by the complex heterogeneity of the disease. Recent efforts to classify subphenotypes of asthma have focused on sputum cellular inflammation profiles, as well as cluster analyses of clinical variables and molecular and genetic signatures. Researchers and clinicians can now evaluate biomarkers of TH2-driven airway inflammation in asthmatic patients, such as serum IgE levels, sputum eosinophil counts, fraction of exhaled nitric oxide levels, and serum periostin levels, to aid decision making in clinical trials and drug development and to identify subsets of patients who might benefit from therapies. Although it is unlikely that these therapies will benefit all asthmatic patients with this heterogeneous disease, advances in understanding asthma subphenotypes in relation to clinical variables and TH2 cytokine responses offer the opportunity to improve the efficacy and safety of proposed therapies for asthma. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: October 2012. Credit may be obtained for these courses until September 30, 2014.Copyright Statement: Copyright © 2012-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Jennifer L. Ingram, PhD, and Monica Kraft, MDActivity Objectives1.To understand the central role that IL-13 plays in asthma pathogenesis.2.To appreciate the heterogeneity of asthma phenotypes and the challenges inherent in devising rational molecular therapies.3.To recognize various strategies to target IL-13 as a promising therapeutic approach in asthma.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: M. Kraft has received research support from the National Institutes of Health, Genentech, GlaxoSmithKline, Merck, Asthmatx, Scientic, Eurmedics, and Novartis and has received other financial assistance from the American Thoracic Society. J. L. Ingram declares that she has no relevant conflicts of interest. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: October 2012. Credit may be obtained for these courses until September 30, 2014. Copyright Statement: Copyright © 2012-2014. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Jennifer L. Ingram, PhD, and Monica Kraft, MD Activity Objectives1.To understand the central role that IL-13 plays in asthma pathogenesis.2.To appreciate the heterogeneity of asthma phenotypes and the challenges inherent in devising rational molecular therapies.3.To recognize various strategies to target IL-13 as a promising therapeutic approach in asthma. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. Kraft has received research support from the National Institutes of Health, Genentech, GlaxoSmithKline, Merck, Asthmatx, Scientic, Eurmedics, and Novartis and has received other financial assistance from the American Thoracic Society. J. L. Ingram declares that she has no relevant conflicts of interest. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Nearly 15 years ago, 2 landmark articles demonstrated IL-13 to be a “central mediator of allergic asthma.”1Wills-Karp M. Luyimbazi J. Xu X. Schofield B. Neben T.Y. Karp C.L. et al.Interleukin-13: central mediator of allergic asthma.Science. 1998; 282: 2258-2261Crossref PubMed Scopus (1735) Google Scholar, 2Grunig G. Warnock M. Wakil A.E. Venkayya R. Brombacher F. Rennick D.M. et al.Requirement for IL-13 independently of IL-4 in experimental asthma.Science. 1998; 282: 2261-2263Crossref PubMed Scopus (1307) Google Scholar Although it has long been recognized that TH2 lymphocytes and cytokines play an important role in directing the allergic response in asthmatic patients, the mechanisms by which these cytokines mediate responses in these patients were not fully understood until the development of allergic murine models of IL-13 blockade and overexpression. The data to support the title statement at the time and since then have shown that IL-13 alone is sufficient to induce responses in murine models of allergen challenge that have a striking resemblance to human asthma. Since that publication, the field has made great strides in understanding how this potent TH2 cytokine directs airway inflammation, airway remodeling, and asthma pathogenesis. Support for IL-13 as a central mediator of human asthma has accumulated because we now know that IL13 and IL-4 receptor (IL4R) polymorphisms are associated with asthma susceptibility3Bottema R.W. Nolte I.M. Howard T.D. Koppelman G.H. Dubois A.E. de Meer G. et al.Interleukin 13 and interleukin 4 receptor-alpha polymorphisms in rhinitis and asthma.Int Arch Allergy Immunol. 2010; 153: 259-267Crossref PubMed Scopus (32) Google Scholar and that a variety of IL-13–induced pathways are also associated with allergy and airway responses in asthmatic patients.4Kuperman D.A. Schleimer R.P. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma.Curr Mol Med. 2008; 8: 384-392Crossref PubMed Scopus (56) Google Scholar, 5Brightling C.E. Saha S. Hollins F. Interleukin-13: prospects for new treatments.Clin Exp Allergy. 2010; 40: 42-49PubMed Google Scholar Despite progress in the understanding of the basic biology of IL-13 in asthma, our field is just beginning to see rewards in the development of promising therapies that target IL-13 and its signaling pathway in asthma. One potential reason for the delay in the development of IL-13–targeted therapies is the complex heterogeneity of asthma, an aspect of the disease that has become increasingly appreciated by clinical scientists. Although IL-13 is a critical mediator of allergic asthma, it might not be the only important mediator driving asthmatic responses in all patients; thus progress in recognizing patient subphenotypes is essential to our understanding of how to direct treatment for asthma. In this review we will describe the gains that have been made in understanding the role of IL-13 in allergic asthma and developing targeted therapies toward IL-13 and its pathway in patients with airways disease and in how knowledge of specific patient phenotypes can expand efficacy for these therapies. Allergic asthma is the most common and well-characterized manifestation of the syndrome. The immune response to allergen exposure in the asthmatic airway is complex and involves many cell types. These processes have been reviewed elsewhere.6Kraft M. Asthma phenotypes and interleukin-13—moving closer to personalized medicine.N Engl J Med. 2011; 365: 1141-1144Crossref PubMed Scopus (16) Google Scholar, 7Locksley R.M. Asthma and allergic inflammation.Cell. 2010; 140: 777-783Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar As stated above, abundant evidence has shown that IL-13 directs many of the processes involved in the allergic asthmatic response (Fig 1). In the current model of allergic airway inflammation, inhaled allergen initiates activation of mast cells. TH2 cells secrete IL-4 and IL-13, driving IgE isotype switching in B cells.8Van der Pouw Kraan T.C. Van der Zee J.S. Boeije L.C. De Groot E.R. Stapel S.O. Aarden L.A. The role of IL-13 in IgE synthesis by allergic asthma patients.Clin Exp Immunol. 1998; 111: 129-135Crossref PubMed Scopus (48) Google Scholar Airway epithelial cells also produce IL-33 and IL-25, which activate dendritic cells and promote release of abundant IL-13 and IL-5 from innate lymphoid cells.9Besnard A.G. Togbe D. Guillou N. Erard F. Quesniaux V. Ryffel B. IL-33-activated dendritic cells are critical for allergic airway inflammation.Eur J Immunol. 2011; 41: 1675-1686Crossref PubMed Scopus (51) Google Scholar, 10Smithgall M.D. Comeau M.R. Yoon B.R. Kaufman D. Armitage R. Smith D.E. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells.Int Immunol. 2008; 20: 1019-1030Crossref PubMed Scopus (196) Google Scholar, 11Ikeda K. Nakajima H. Suzuki K. Kagami S. Hirose K. Suto A. et al.Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation.Blood. 2003; 101: 3594-3596Crossref PubMed Scopus (108) Google Scholar, 12Wang Y.H. Angkasekwinai P. Lu N. Voo K.S. Arima K. Hanabuchi S. et al.IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.J Exp Med. 2007; 204: 1837-1847Crossref PubMed Scopus (237) Google Scholar, 13Bartemes K.R. Iijima K. Kobayashi T. Kephart G.M. McKenzie A.N. Kita H. IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs.J Immunol. 2012; 188: 1503-1513Crossref PubMed Scopus (58) Google Scholar, 14Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (127) Google Scholar IL-13 production in the airway promotes the survival and migration of eosinophils,15Pope S.M. Brandt E.B. Mishra A. Hogan S.P. Zimmermann N. Matthaei K.I. et al.IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism.J Allergy Clin Immunol. 2001; 108: 594-601Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar activation of macrophages,16Martinez-Nunez R.T. Louafi F. Sanchez-Elsner T. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptor alpha1 (IL13Ralpha1).J Biol Chem. 2011; 286: 1786-1794Crossref PubMed Scopus (49) Google Scholar increased permeability of and mucus production by airway epithelial cells,17Ramirez-Icaza G. Mohammed K.A. Nasreen N. Van Horn R.D. Hardwick J.A. Sanders K.L. et al.Th2 cytokines IL-4 and IL-13 downregulate paxillin expression in bronchial airway epithelial cells.J Clin Immunol. 2004; 24: 426-434Crossref PubMed Scopus (10) Google Scholar, 18Zhu Z. Homer R.J. Wang Z. Chen Q. Geba G.P. Wang J. et al.Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.J Clin Invest. 1999; 103: 779-788Crossref PubMed Google Scholar production of inducible nitric oxide synthase by airway epithelial cells,19Chibana K. Trudeau J.B. Mustovich A.T. Hu H. Zhao J. Balzar S. et al.IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells.Clin Exp Allergy. 2008; 38: 936-946Crossref PubMed Scopus (34) Google Scholar and transformation of airway fibroblasts to myofibroblasts,18Zhu Z. Homer R.J. Wang Z. Chen Q. Geba G.P. Wang J. et al.Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.J Clin Invest. 1999; 103: 779-788Crossref PubMed Google Scholar leading to collagen deposition.18Zhu Z. Homer R.J. Wang Z. Chen Q. Geba G.P. Wang J. et al.Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.J Clin Invest. 1999; 103: 779-788Crossref PubMed Google Scholar IL-13 also stimulates airways hyperresponsiveness.20Kuperman D.A. Huang X. Koth L.L. Chang G.H. Dolganov G.M. Zhu Z. et al.Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma.Nat Med. 2002; 8: 885-889Crossref PubMed Google Scholar Therefore, considering the importance of TH2 cytokines, specifically IL-13, in the complex immune response mounted by susceptible patients with allergic asthma, this cytokine is certainly a relevant target for asthma therapy. However, many other airway cell types and pathways are involved in the allergen immune response, and these pathways might be key in the expression of the different asthma phenotypes. A complex receptor system mediates the signaling of IL-13 and IL-4 (Fig 2). Four heterodimeric receptor complexes have been identified that bind to IL-4, IL-13, or both. The IL-4Rα subunit is a component of both the type I and type II receptors. Type I receptors are composed of the IL-4Rα subunit complexed with the common γ chain. These type I receptors bind to IL-4 on cells of hematopoietic stem cell origin. The common γ chain does not bind IL-4 or IL-13, but it is important for signaling of the type I receptor. In this complex IL-4 first binds to the IL-4Rα subunit, and then the common γ chain is recruited to form the complex. Both IL-4 and IL-13 bind to and signal through the type II receptor, a heterodimer comprised of the IL-4Rα subunit and the IL-13 receptor (IL-13R) alpha 1 subunit, which is found on cells of nonhematopoietic stem cell origin. In this complex IL-4 binds to the IL-4Rα subunit, which then recruits the IL-13Rα1 subunit to form the heterodimer. Alternatively, IL-13 first binds to the IL-13Rα1 subunit and recruits the IL-4Rα subunit to form the stable heterodimer.21LaPorte S.L. Juo Z.S. Vaclavikova J. Colf L.A. Qi X. Heller N.M. et al.Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.Cell. 2008; 132: 259-272Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Both the type I and type II receptor complexes signal through a tyrosine kinase (Tyk)/Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascade. Activation of these proteins by IL-13 phosphorylates intracellular tyrosines, resulting in recruitment of STAT6 to the receptor complex. STAT6 is then phosphorylated and activated, resulting in translocation of STAT6 to the nucleus for binding to specific DNA elements on the promoter regions of downstream genes for initiation of transcription.22Goenka S. Kaplan M.H. Transcriptional regulation by STAT6.Immunol Res. 2011; 50: 87-96Crossref PubMed Scopus (32) Google Scholar Although STAT6 is the well-recognized primary mediator of IL-13– and IL-4–induced gene expression, studies of gene-deficient mice have revealed that other transcription factors, such as STAT1,23Ingram J.L. Antao-Menezes A. Mangum J.B. Lyght O. Lee P.J. Elias J.A. et al.Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response-1 and platelet-derived growth factor ligands in pulmonary fibroblasts.J Immunol. 2006; 177: 4141-4148PubMed Google Scholar, 24Wang I.M. Lin H. Goldman S.J. Kobayashi M. STAT-1 is activated by IL-4 and IL-13 in multiple cell types.Mol Immunol. 2004; 41: 873-884Crossref PubMed Scopus (26) Google Scholar STAT3,25Hecker M. Zaslona Z. Kwapiszewska G. Niess G. Zakrzewicz A. Hergenreider E. et al.Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension.Am J Respir Crit Care Med. 2010; 182: 805-818Crossref PubMed Scopus (20) Google Scholar and early growth response 1,23Ingram J.L. Antao-Menezes A. Mangum J.B. Lyght O. Lee P.J. Elias J.A. et al.Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response-1 and platelet-derived growth factor ligands in pulmonary fibroblasts.J Immunol. 2006; 177: 4141-4148PubMed Google Scholar, 26Cho S.J. Kang M.J. Homer R.J. Kang H.R. Zhang X. Lee P.J. et al.Role of early growth response-1 (Egr-1) in interleukin-13-induced inflammation and remodeling.J Biol Chem. 2006; 281: 8161-8168Crossref PubMed Scopus (58) Google Scholar also mediate IL-13–induced functions. A third IL-13 receptor is the IL-13Rα2 subunit. This subunit binds only to IL-13 and in mice exists in both membrane-bound and soluble forms.27Chen W. Sivaprasad U. Tabata Y. Gibson A.M. Stier M.T. Finkelman F.D. et al.IL-13R alpha 2 membrane and soluble isoforms differ in humans and mice.J Immunol. 2009; 183: 7870-7876Crossref PubMed Scopus (17) Google Scholar, 28O'Toole M. Legault H. Ramsey R. Wynn T.A. Kasaian M.T. A novel and sensitive ELISA reveals that the soluble form of IL-13R-alpha2 is not expressed in plasma of healthy or asthmatic subjects.Clin Exp Allergy. 2008; 38: 594-601Crossref PubMed Scopus (17) Google Scholar A soluble form of IL-13Rα2 has not been detected in human subjects.27Chen W. Sivaprasad U. Tabata Y. Gibson A.M. Stier M.T. Finkelman F.D. et al.IL-13R alpha 2 membrane and soluble isoforms differ in humans and mice.J Immunol. 2009; 183: 7870-7876Crossref PubMed Scopus (17) Google Scholar, 28O'Toole M. Legault H. Ramsey R. Wynn T.A. Kasaian M.T. A novel and sensitive ELISA reveals that the soluble form of IL-13R-alpha2 is not expressed in plasma of healthy or asthmatic subjects.Clin Exp Allergy. 2008; 38: 594-601Crossref PubMed Scopus (17) Google Scholar IL-13 binds with much higher affinity to IL-13Rα2 than to the IL-13Rα1 subunit.29Donaldson D.D. Whitters M.J. Fitz L.J. Neben T.Y. Finnerty H. Henderson S.L. et al.The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1.J Immunol. 1998; 161: 2317-2324PubMed Google Scholar, 30Caput D. Laurent P. Kaghad M. Lelias J.M. Lefort S. Vita N. et al.Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor alpha chain.J Biol Chem. 1996; 271: 16921-16926Crossref PubMed Scopus (230) Google Scholar The high affinity of IL-13 for binding to IL-13Rα2 and the lack of evidence for signaling activity for this receptor subunit have led to the hypothesis that IL-13Rα2 is a decoy receptor. Studies of lung-targeted IL-13 transgenic mice with IL-13Rα2 null loci indicated that IL-13Rα2 deficiency significantly augmented IL-13– or ovalbumin-induced pulmonary inflammation and remodeling.31Zheng T. Liu W. Oh S.Y. Zhu Z. Hu B. Homer R.J. et al.IL-13 receptor alpha2 selectively inhibits IL-13-induced responses in the murine lung.J Immunol. 2008; 180: 522-529PubMed Google Scholar IL-13Rα2 effectively attenuated IL-13–induced eotaxin and STAT6 phosphorylation in human bronchial fibroblasts. Furthermore, although IL-13Rα2 does not directly bind to IL-4, it has been shown to physically interact with IL-4Rα in an IL-4–dependent manner in human bronchial fibroblasts, thus potentially suppressing IL-4–mediated functions in the airway.32Andrews A.L. Nasir T. Bucchieri F. Holloway J.W. Holgate S.T. Davies D.E. IL-13 receptor alpha 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts.J Allergy Clin Immunol. 2006; 118: 858-865Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar We have reported that cell-surface expression of IL-13Rα2 on human asthmatic airway fibroblasts was reduced compared with expression on normal control airway fibroblasts, supporting the hypothesis that IL-13Rα2 is a negative regulator of IL-13–induced responses in asthmatic patients.33Ingram J.L. Huggins M.J. Church T.D. Li Y. Francisco D.C. Degan S. et al.Airway fibroblasts in asthma manifest an invasive phenotype.Am J Respir Crit Care Med. 2011; 183: 1625-1632Crossref PubMed Scopus (11) Google Scholar However, the concept of IL-13Rα2 as a decoy receptor has lately come under question because recent studies have reported that IL-13Rα2 has the capacity to mediate IL-13 signaling.34Fichtner-Feigl S. Strober W. Kawakami K. Puri R.K. Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis.Nat Med. 2006; 12: 99-106Crossref PubMed Scopus (319) Google Scholar, 35Mandal D. Levine A.D. Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway.Inflamm Bowel Dis. 2010; 16: 753-764Crossref PubMed Scopus (16) Google Scholar, 36Fujisawa T. Joshi B. Nakajima A. Puri R.K. A novel role of interleukin-13 receptor alpha2 in pancreatic cancer invasion and metastasis.Cancer Res. 2009; 69: 8678-8685Crossref PubMed Scopus (28) Google Scholar In a murine model of bleomycin-induced fibrosis, in vivo silencing of IL-13Rα2 with gene-specific small interfering RNAs (siRNAs) resulted in significantly reduced production of TGF-β1 and deposition of collagen in the lungs of mice.34Fichtner-Feigl S. Strober W. Kawakami K. Puri R.K. Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis.Nat Med. 2006; 12: 99-106Crossref PubMed Scopus (319) Google Scholar Also, an intriguing recent study of IL-13 signaling in colorectal cancer lesions demonstrated that IL-13Rα2 can serve dual functions as both a decoy receptor and a mediator of mitogen-activated protein kinase signaling.35Mandal D. Levine A.D. Elevated IL-13Ralpha2 in intestinal epithelial cells from ulcerative colitis or colorectal cancer initiates MAPK pathway.Inflamm Bowel Dis. 2010; 16: 753-764Crossref PubMed Scopus (16) Google Scholar Thus these studies call into question the dogma of IL-13Rα2 as a decoy receptor and suggest that IL-13Rα2 can serve as a signaling receptor in some cell types. All 3 of the IL-13 receptor subunits are targets for directed therapies in the treatment of asthma and allergy. Pioneering and comprehensive studies of targeted and inducible pulmonary overexpression of IL-13 transgenic mice by Elias et al18Zhu Z. Homer R.J. Wang Z. Chen Q. Geba G.P. Wang J. et al.Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.J Clin Invest. 1999; 103: 779-788Crossref PubMed Google Scholar, 37Lee C.G. Homer R.J. Zhu Z. Lanone S. Wang X. Koteliansky V. et al.Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).J Exp Med. 2001; 194: 809-821Crossref PubMed Scopus (473) Google Scholar have defined the role of IL-13 in directing cellular and molecular responses that might be relevant to airway inflammation and remodeling in human allergic asthma. These mechanistic studies have shown that IL-13 expression alone stimulates many of the key inflammatory, remodeling, and physiologic features of human asthma, including airway eosinophilia, mucus hypersecretion, subepithelial airway fibrosis, and methacholine airway hyperresponsiveness.18Zhu Z. Homer R.J. Wang Z. Chen Q. Geba G.P. Wang J. et al.Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.J Clin Invest. 1999; 103: 779-788Crossref PubMed Google Scholar Furthermore, these studies revealed signaling pathways and specific mechanisms by which IL-13 directs its effects in the lung.18Zhu Z. Homer R.J. Wang Z. Chen Q. Geba G.P. Wang J. et al.Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.J Clin Invest. 1999; 103: 779-788Crossref PubMed Google Scholar, 37Lee C.G. Homer R.J. Zhu Z. Lanone S. Wang X. Koteliansky V. et al.Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1).J Exp Med. 2001; 194: 809-821Crossref PubMed Scopus (473) Google Scholar In addition, a study of lung-specific transgenic IL-9–expressing mice led to the conclusion that airway epithelial cells were a significant source of IL-13 expression.38Temann U.A. Laouar Y. Eynon E.E. Homer R. Flavell R.A. IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells.Int Immunol. 2007; 19: 1-10Crossref PubMed Scopus (37) Google Scholar All of these IL-13–driven processes and mechanisms have subsequently been found to be important to human asthma and lung disease; thus these studies of IL-13 transgenic mice have been an essential tool to lay the foundation for ongoing work to further investigate the effects of IL-13 in directing human airway inflammation. To this end, investigations of human cells and tissues have demonstrated that IL-13 is a key cytokine associated with asthma, correlating IL-13 expression with physiologic measurements of lung function and severity in asthmatic patients. Table I ∗References 3Bottema R.W. Nolte I.M. Howard T.D. Koppelman G.H. Dubois A.E. de Meer G. et al.Interleukin 13 and interleukin 4 receptor-alpha polymorphisms in rhinitis and asthma.Int Arch Allergy Immunol. 2010; 153: 259-267Crossref PubMed Scopus (32) Google Scholar, 8Van der Pouw Kraan T.C. Van der Zee J.S. Boeije L.C. De Groot E.R. Stapel S.O. Aarden L.A. The role of IL-13 in IgE synthesis by allergic asthma patients.Clin Exp Immunol. 1998; 111: 129-135Crossref PubMed Scopus (48) Google Scholar, 14Mjosberg J.M. Trifari S. Crellin N.K. Peters C.P. van Drunen C.M. Piet B. et al.Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.Nat Immunol. 2011; 12: 1055-1062Crossref PubMed Scopus (127) Google Scholar, 15Pope S.M. Brandt E.B. Mishra A. Hogan S.P. Zimmermann N. Matthaei K.I. et al.IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism.J Allergy Clin Immunol. 2001; 108: 594-601Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 16Martinez-Nunez R.T. Louafi F. Sanchez-Elsner T. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct target" @default.
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• W1979732414 title "IL-13 in asthma and allergic disease: Asthma phenotypes and targeted therapies" @default.
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