{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:50:38Z","timestamp":1789386638325,"version":"build-2803163510"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2009,8,1]],"date-time":"2009-08-01T00:00:00Z","timestamp":1249084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Allergic asthma is caused by inhaled allergens and is characterized by airway eosinophilia, as well as mucus hypersecretion, which can lead to airflow obstruction. Despite the association of increased IL-6 levels with human atopic asthma, the contribution of IL-6 to the development of allergic airway inflammation triggered by inhaled allergens remains unclear. In this study, we examined the role of IL-6 in a mouse model of allergic airway inflammation induced by direct airway exposure to extracts of Aspergillus fumigatus, a common allergen in humans. We show that inhaled A. fumigatus extracts rapidly trigger the production of IL-6 in the airways. IL-6 appears to be dispensable for the recruitment of eosinophils to the lung during the development of allergic airway inflammation. However, IL-6 is essential for mucus hypersecretion by airway epithelial cells triggered in response to inhaled A. fumigatus Ags. Impaired mucus production caused by IL-6 deficiency correlates with a severe reduction in the levels of IL-13, a major inducer of mucin glycoproteins. Thus, IL-6 is a key regulator of specific hallmark features of allergic airway inflammation and it could be a potential target for pulmonary diseases that are associated with goblet cell metaplasia and mucus hypersecretion.<\/jats:p>","DOI":"10.4049\/jimmunol.0802923","type":"journal-article","created":{"date-parts":[[2009,7,11]],"date-time":"2009-07-11T01:40:49Z","timestamp":1247276449000},"page":"1732-1738","source":"Crossref","is-referenced-by-count":120,"title":["IL-6 Is Required for Airway Mucus Production Induced by Inhaled Fungal Allergens"],"prefix":"10.1093","volume":"183","author":[{"given":"Wendy A","family":"Neveu","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Immunobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna B","family":"Allard","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont , Burlington VT 05405"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Dienz","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Wargo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont , Burlington VT 05405"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennaro","family":"Ciliberto","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche di Biologia Molecolare P. Angeletti , Roma,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie A","family":"Whittaker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary Disease and Critical Care, University of Vermont , Burlington VT 05405"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Rincon","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,8,1]]},"reference":[{"key":"2025032709085318000_R1","first-page":"1","article-title":"Interleukin-6: from basic science to medicine\u201340 years in immunology.","volume-title":"Annu. Rev. Immunol.","year":"2005"},{"key":"2025032709085318000_R2","first-page":"804","article-title":"Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1.","volume-title":"Immunity","year":"2000"},{"key":"2025032709085318000_R3","first-page":"39","article-title":"Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation.","volume-title":"J. Exp. Med.","year":"2002"},{"key":"2025032709085318000_R4","first-page":"2720","article-title":"IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032709085318000_R5","first-page":"179","article-title":"TGF\u03b2 in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.","volume-title":"Immunity","year":"2006"},{"key":"2025032709085318000_R6","first-page":"235","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.","volume-title":"Nature","year":"2006"},{"key":"2025032709085318000_R7","first-page":"231","article-title":"Transforming growth factor-\u03b2 induces development of the T(H)17 lineage.","volume-title":"Nature","year":"2006"},{"key":"2025032709085318000_R8","first-page":"2041","article-title":"Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032709085318000_R9","first-page":"1033","article-title":"Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.","volume-title":"Science","year":"2003"},{"key":"2025032709085318000_R10","first-page":"2829","article-title":"Synthesis of germ-line \u03b31 immunoglobulin heavy-chain transcripts in resting B cells: induction by interleukin 4 and inhibition by interferon \u03b3.","volume-title":"Proc. Nat. Acad. Sci. USA","year":"1989"},{"key":"2025032709085318000_R11","first-page":"255","article-title":"Immunologic basis of antigen-induced airway hyperresponsiveness.","volume-title":"Annu. Rev. Immunol.","year":"1999"},{"key":"2025032709085318000_R12","first-page":"593","article-title":"Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9.","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"2002"},{"key":"2025032709085318000_R13","first-page":"2258","article-title":"Interleukin-13: central mediator of allergic asthma.","volume-title":"Science","year":"1998"},{"key":"2025032709085318000_R14","first-page":"4668","article-title":"Critical role for IL-13 in the development of allergen-induced airway hyperreactivity.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032709085318000_R15","first-page":"454","article-title":"The biological functions of T helper 17 cell effector cytokines in inflammation.","volume-title":"Immunity","year":"2008"},{"key":"2025032709085318000_R16","first-page":"2715","article-title":"Interleukin-17 is a negative regulator of established allergic asthma.","volume-title":"J. Exp. Med.","year":"2006"},{"key":"2025032709085318000_R17","first-page":"375","article-title":"Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses.","volume-title":"Immunity","year":"2002"},{"key":"2025032709085318000_R18","first-page":"960","article-title":"T cells and cytokines in bronchoalveolar lavage fluid after segmental allergen provocation in atopic asthma.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"1995"},{"key":"2025032709085318000_R19","first-page":"1354","article-title":"Circulating interleukin-6 levels in patients with bronchial asthma.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"1995"},{"key":"2025032709085318000_R20","first-page":"1001","article-title":"Expression of potent inflammatory cytokines, granulocytic-macrophage-colony-stimulating factor and interleukin-6 in bronchial epithelial cells of patients with asthma.","volume-title":"J. Allergy Clin. Immunol.","year":"1992"},{"key":"2025032709085318000_R21","first-page":"4051","article-title":"Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation.","volume-title":"J. Immunol.","year":"2000"},{"key":"2025032709085318000_R22","first-page":"1321","article-title":"Enhanced airway inflammation and decreased subepithelial fibrosis in interleukin 6-deficient mice following chronic exposure to aerosolized antigen.","volume-title":"Clin. Exp. Allergy","year":"2004"},{"key":"2025032709085318000_R23","first-page":"313","article-title":"The IL-6R\u03b1 chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.","volume-title":"J. Clin. Invest.","year":"2005"},{"key":"2025032709085318000_R24","first-page":"310","article-title":"Aspergillus fumigatus and aspergillosis.","volume-title":"Clin. Microbiol. Rev.","year":"1999"},{"key":"2025032709085318000_R25","first-page":"1189","article-title":"Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion.","volume-title":"EMBO J.","year":"1994"},{"key":"2025032709085318000_R26","first-page":"69","article-title":"The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.","volume-title":"J. Exp. Med.","year":"2009"},{"key":"2025032709085318000_R27","first-page":"5186","article-title":"Aspergillus fumigatus generates an enhanced Th2-biased immune response in mice with defective cystic fibrosis transmembrane conductance regulator.","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032709085318000_R28","first-page":"6257","article-title":"A prominent role for airway epithelial NF-kappa B activation in lipopolysaccharide-induced airway inflammation.","volume-title":"J. Immunol.","year":"2003"},{"key":"2025032709085318000_R29","first-page":"1145","article-title":"Cytokine production from sputum cells after allergenic challenge in IgE-mediated asthma.","volume-title":"Allergy","year":"2002"},{"key":"2025032709085318000_R30","first-page":"285","article-title":"Allergen detection from 11 fungal species before and after germination.","volume-title":"J. Allergy Clin. Immunol.","year":"2003"},{"key":"2025032709085318000_R31","first-page":"3905","article-title":"Adjuvant-induced arthritis: IL-1\u03b2, IL-6 and TNF-\u03b1 are up-regulated in the spinal cord.","volume-title":"NeuroReport","year":"2001"},{"key":"2025032709085318000_R32","first-page":"223","article-title":"Influences of anti-mouse interleukin-6 receptor antibody on immune responses in mice.","volume-title":"Immunol. Lett.","year":"2002"},{"key":"2025032709085318000_R33","first-page":"17","article-title":"Cutting edge: inflammasome activation by alum and alum\u2019s adjuvant effect are mediated by NLRP3.","volume-title":"J. Immunol.","year":"2008"},{"key":"2025032709085318000_R34","first-page":"1122","article-title":"Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants.","volume-title":"Nature","year":"2008"},{"key":"2025032709085318000_R35","first-page":"1110","article-title":"Identification of IL-5 and RANTES as the major eosinophil chemoattractants in the asthmatic lung.","volume-title":"J. Allergy Clin. Immunol.","year":"1996"},{"key":"2025032709085318000_R36","first-page":"291","article-title":"Eotaxin: an essential mediator of eosinophil trafficking into mucosal tissues.","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"1999"},{"key":"2025032709085318000_R37","first-page":"625","article-title":"Various immunological phenotypes are associated with increased airway responsiveness.","volume-title":"Clin. Exp. Allergy.","year":"1998"},{"key":"2025032709085318000_R38","first-page":"4538","article-title":"B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells.","volume-title":"J. Immunol.","year":"1986"},{"key":"2025032709085318000_R39","first-page":"1726","article-title":"Serological, biochemical, and functional identity of B cell-stimulatory factor 1 and B cell differentiation factor for IgG1.","volume-title":"J. Exp. Med.","year":"1985"},{"key":"2025032709085318000_R40","first-page":"461","article-title":"Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.","volume-title":"J. Exp. Med.","year":"1997"},{"key":"2025032709085318000_R41","first-page":"3597","article-title":"Inhibition of NFAT specifically in T cells prevents allergic pulmonary inflammation.","volume-title":"J. Immunol.","year":"2004"},{"key":"2025032709085318000_R42","first-page":"1630","article-title":"A critical role for IL-21 in regulating immunoglobulin production.","volume-title":"Science","year":"2002"},{"key":"2025032709085318000_R43","first-page":"5154","article-title":"Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells.","volume-title":"J. Immunol.","year":"2004"},{"key":"2025032709085318000_R44","first-page":"4565","article-title":"Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C\u03b5 transcription of IL-4-stimulated B cells.","volume-title":"Blood","year":"2002"},{"key":"2025032709085318000_R45","first-page":"8554","article-title":"IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice.","volume-title":"J. Immunol.","year":"2007"},{"key":"2025032709085318000_R46","first-page":"241","article-title":"Airway mucus hypersecretion in asthma: an undervalued pathology?.","volume-title":"Curr. Opin. Pharmacol.","year":"2004"},{"key":"2025032709085318000_R47","first-page":"779","article-title":"Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.","volume-title":"J. Clin. Invest.","year":"1999"},{"key":"2025032709085318000_R48","first-page":"3796","article-title":"IL-4 directs the development of Th2-like helper effectors.","volume-title":"J. Immunol.","year":"1990"},{"key":"2025032709085318000_R49","first-page":"1001","article-title":"Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma.","volume-title":"J. Allergy Clin. Immunol.","year":"1992"},{"key":"2025032709085318000_R50","first-page":"1110","article-title":"Intrinsic biochemical and functional differences in bronchial epithelial cells of children with asthma.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"2006"},{"key":"2025032709085318000_R51","first-page":"958","article-title":"Cytokines in symptomatic asthma airways.","volume-title":"J. Allergy Clin. Immunol.","year":"1992"},{"key":"2025032709085318000_R52","first-page":"487","article-title":"Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmaticus.","volume-title":"Am. J. Respir. Crit. Care Med.","year":"1999"},{"key":"2025032709085318000_R53","first-page":"307","article-title":"Cellular and cytokine immunoregulation in patients with chronic obstructive pulmonary disease and bronchial asthma.","volume-title":"Mediators Iinflamm.","year":"2002"},{"key":"2025032709085318000_R54","first-page":"361","article-title":"Lower airway disease in asthmatics with and without rhinitis.","volume-title":"Lung","year":"2008"},{"key":"2025032709085318000_R55","first-page":"399","article-title":"Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma.","volume-title":"J. Appl. Physiol.","year":"2007"},{"key":"2025032709085318000_R56","first-page":"505","article-title":"Mucins, mucus, and sputum.","volume-title":"Chest","year":"2009"},{"key":"2025032709085318000_R57","first-page":"17036","article-title":"Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine\/autocrine loop.","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2025032709085318000_R58","first-page":"339","article-title":"Impaired immune and acute-phase responses in interleukin-6-deficient mice.","volume-title":"Nature","year":"1994"},{"key":"2025032709085318000_R59","first-page":"27","article-title":"The effects of IL-6 on CD4 T cell responses.","volume-title":"Clin. Immunol.","year":"2009"},{"key":"2025032709085318000_R60","first-page":"1608","article-title":"STAT3 mutations in the hyper-IgE syndrome.","volume-title":"N. Engl. J. Med.","year":"2007"},{"key":"2025032709085318000_R61","first-page":"1058","article-title":"Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.","volume-title":"Nature","year":"2007"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/3\/1732\/62691660\/9381.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/183\/3\/1732\/62691660\/9381.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T10:58:35Z","timestamp":1743332315000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/183\/3\/1732\/8053458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,8,1]]},"references-count":61,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2009,8,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0802923","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,8]]},"published":{"date-parts":[[2009,8,1]]}}}