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IL-5 Regulate Airways Hyperreactivity Integrated Signals Between IL-13 Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity Dianne C. Webb, Andrew N. J. McKenzie, Aulikki M. L. Koskinen, Ming Yang, Joërg Mattes and Paul S. Foster This information is current as of September 25, 2021. J Immunol 2000; 165:108-113; ; doi: 10.4049/jimmunol.165.1.108 http://www.jimmunol.org/content/165/1/108 Downloaded from References This article cites 48 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/165/1/108.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity Dianne C. Webb,* Andrew N. J. McKenzie,† Aulikki M. L. Koskinen,* Ming Yang,* Joe¨rg Mattes,* and Paul S. Foster1* In this investigation, we have examined the integrated relationship between IL-13, IL-4, and IL-5 for the development of airways hyperreactivity (AHR) in a model of asthma in BALB/c mice. Sensitization and aeroallergen challenge of both wild-type (WT) and IL-13 gene-targeted (IL-13؊/؊) mice induced allergic disease that was characterized by pulmonary eosinophilia and AHR to methacholine. Although these responses in IL-13؊/؊ mice were heightened compared with WT, they could be reduced to the-␤ level in nonallergic mice by the concomitant neutralization of IL-4. Mice in which both IL-4 and IL-13 were depleted displayed a marked reduction in tissue eosinophils, despite the development of a blood eosinophilia. Similar neutralization of IL-4 in WT ؊ ؊ mice only partially reduced AHR with no effect on tissue eosinophilia. In addition, neutralization of IL-5 in IL-13 / mice, but Downloaded from not in WT mice, inhibited AHR, suggesting that tissue eosinophilia is linked to the mechanism underlying AHR only in the absence ,of IL-13. Additionally, mucus hypersecretion was attenuated in IL-13؊/؊ mice, despite the persistence of AHR. Taken together our data suggest both a modulatory role for IL-13 during sensitization and a proinflammatory role during aeroallergen challenge. The latter process appears redundant with respect to IL-4. The Journal of Immunology, 2000, 165: 108–113. llergic asthma is characterized clinically by the hyper- anism regulating AHR independently of IL-4 and IL-5 is depen- http://www.jimmunol.org/ secretion of mucus, obstruction, and inflammation of the dent on Th2 cells (16). Evidence is now emerging that Stat6-me- airways; enhanced bronchial reactivity (airways hyper- diated signaling by the IL-4R␣ subunit is critical for the A 2 reactivity, AHR ) to spasmogenic stimuli; and elevated serum IgE development of enhanced bronchial reactivity in murine models of (1, 2). Although this inflammatory response is complex, clinical asthma (21–25). Thus, there appears to be an IL-4-independent, and experimental investigations have highlighted the obligatory but IL-4R␣-dependent mechanism for the activation of Stat6 and ϩ role of CD4 Th2 lymphocytes and the importance of eosinophils the induction of AHR. in the etiology of asthma (3–6). A strong correlation has been Recently, IL-13, which also stimulates the activation of Stat6 by demonstated between the severity of disease and the level of these signal transduction through the IL-4R␣ subunit, has been shown to by guest on September 25, 2021 leukocytes and their products in the lung (3–5, 7–9). The Th2-type mediate AHR in the allergic lung (24, 26). However, there appears cytokines IL-4 and IL-5 have been directly linked with the immu- to be a temporal relationship in the requirement for either IL-4 or nopathogenesis of asthma (2–4, 10), and murine models have also IL-13 for the development of AHR. Blockade of IL-13, but not provided corroborative evidence of the importance of these cyto- IL-4, before aeroallergen challenge is sufficient to attenuate AHR kines as central regulators of allergic disease (11–18). The devel- (11, 24, 26). In addition, while these cytokines induce similar opment of Th2-mediated responses that underlie IgE-dependent physiological responses through their shared usage of the IL-4R␣ inflammation, airway eosinophilia, morphological changes to the subunit, there are distinct mechanisms mediated by either cytokine respiratory epithelium, and AHR has been linked to IL-4 (11, 13, (reviewed in Ref. 27), and this is corroborated by their different 18, 19), while IL-5 directly modulates allergic airways disease by spatial and temporal patterns of expression (28, 29). Therefore, it regulating eosinophilic inflammation (12, 16). However, although is likely that IL-4 may be key regulator for the development of a IL-4 and IL-5 are important regulators of eosinophilia and AHR, Th2 phenotype during sensitization (11), and that IL-13 may be these cytokines are not obligatory for these processes. In contrast Ϫ Ϫ more important for the induction of AHR during allergen inhala- to IL-5 / C57BL/6 mice, an IL-5-independent mechanism reg- tion (24, 26). However, the precise mechanism underlying IL-13- ulates AHR in BALB/c mice deficient in this factor (12, 16). AHR mediated AHR and its integrated relationship with IL-4- and IL- and tissue eosinophilia can also persist in response to allergen Ϫ Ϫ 5-mediated processes is unclear. The induction of AHR in naive provocation of IL-4 / mice (16, 17, 20). Importantly, the mech- mice by rIL-13 has been shown to correlate with eosinophil accu- mulation in the airways in a process dependent on signaling *Division of Biochemistry and Molecular Biology, The John Curtin School of Med- through the IL-4R␣ subunit (24). In contrast, the role of IL-13 in ical Research, Australian National University, Canberra, Australia; and †Medical Re- the development of allergic AHR has been suggested to be disso- search Council Laboratory of Molecular Biology, Cambridge, United Kingdom ciated from eosinophilic inflammation, but implicated in other Received for publication January 21, 2000. Accepted for publication April 14, 2000. pathophysiological manifestations of the asthmatic phenotype The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance (26). Notably, while neutralization of IL-13 during challenge has with 18 U.S.C. Section 1734 solely to indicate this fact. been shown to attenuate mucus hypersecretion concomitantly with 1 Address correspondence and reprint requests to Dr. Paul S. Foster, Division of AHR (26), the intrinsic association of this secretogogenic process Biochemistry and Molecular Biology, The John Curtin School of Medical Research, with AHR is yet to be fully delineated. Australian National University, Canberra, ACT 0200, Australia. E-mail address: Ϫ/Ϫ [email protected] In this investigation, we have employed IL-13 mice to ex- 2 Abbreviations used in this paper: AHR, airways hyperreactivity; PBLN, peribron- amine the role of this cytokine and its integrated relationship with chial lymph node; WT, wild type. IL-4 and IL-5 in the development of pulmonary eosinophilia, Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 109 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 chal- lenge. 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. Materials and Methods Induction of allergic airways inflammation IL-13Ϫ/Ϫ mice were generated from (129 ϫ 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 back- ground. Mice were sensitized at 6 wk of age by i.p. injection with 50 ␮g 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-13Ϫ/Ϫ 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 ␤ GL113) 24 h before the i.p. injection with OVA or Sal and then weekly Downloaded from throughout the experimental period. Abs were administered in sterile sa- line. 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 spe- cific pathogen-free facility. http://www.jimmunol.org/ 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, sec- tioned, and stained with Alcian blue-periodic-acid Schiff for the enumer- ation of mucin-secreting cells or Carbol’s Chromotrope-Hematoxylin for the identification of eosinophils.
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