title: STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria.
abstract: Asthma exacerbations can be caused by a number of factors, including the fungal allergen Alternaria, which is specifically associated with severe and near-fatal attacks. The mechanisms that trigger lung responses are unclear and might vary between allergens. A comparison between Alternaria, Aspergillus, Candida, and house dust mite, all allergens in humans, showed that only Alternaria promoted immediate innate airway eosinophilia within 12 h of inhalation in nonsensitized mice. Alternaria, but not the other allergens, induced a rapid increase in airway levels of IL-33, accompanied by IL-33 receptor (IL-33R)-positive natural helper cell (NHC) production of IL-5 and IL-13. NHCs in the lung and bone marrow constitutively expressed transcription factors [GATA-3 and E26 transformation-specific sequence-1 (ETS-1)] that could allow for rapid induction of T helper type 2 (Th2) cytokines. Lung NHC numbers and proliferation (%Ki-67), but not IL-5 or GATA-3 expression, were significantly reduced in STAT6-deficient mice 3 days after one challenge with Alternaria. Alternaria induced NHC expression of the EGF receptor ligand amphiregulin (partially dependent on STAT6), as well as EGF receptor signaling in the airway epithelium. Finally, human peripheral blood NHCs (CRTH2(+)CD127(+) lineage-negative lymphocytes) from allergic individuals highly expressed GATA-3 and ETS-1, similar to lung NHCs in mice. In summary, Alternaria-induced lung NHC proliferation and expression of amphiregulin are regulated by STAT6. In addition, NHCs in mouse and humans are primed to express Th2 cytokines through constitutive expression of GATA-3 and ETS-1. Thus several transcription factor pathways (STAT6, GATA-3, and ETS-1) may contribute to NHC proliferation and Th2-type responses in Alternaria-induced asthma.
authors.affiliation: Dept. of Medicine, Univ. of California San Diego, Biomedical Sciences Bldg., La Jolla, CA 92093-0635, USA. tdoherty@ucsd.edu
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Doherty
authors.forename: Naseem
authors.initials: N
authors.lastname: Khorram
authors.forename: Jinny E
authors.initials: JE
authors.lastname: Chang
authors.forename: Hee-Kyoo
authors.initials: HK
authors.lastname: Kim
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenthal
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
mesh_terms: D060487:Alternariosis / Q000276:immunology*; D066258:Amphiregulin; D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology; D002177:Candidiasis / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D066255:EGF Family of Proteins; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology; D011657:Pulmonary Eosinophilia / Q000276:immunology; D039981:Pyroglyphidae / Q000276:immunology; D065631:Rhinitis, Allergic; D012221:Rhinitis, Allergic, Perennial / Q000276:immunology; D050800:STAT6 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D016207:Cytokines; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D014157:Transcription Factors