title: Phenotypic and genotypic association of epithelial IL1RL1 to human TH2-like asthma.
abstract: BACKGROUND
  Severe asthma remains poorly characterized, although it likely consists of at least 1 phenotype with features of TH2-like inflammation. IL1RL1, encoding both the IL-33 receptor, ST2L, and decoy receptor, sST2, has been genetically associated with asthma, though the mechanism for susceptibility remains unknown.
  
  
  OBJECTIVE
  Given previous data supporting a role for IL1RL1 in TH2 inflammation, we hypothesized that ST2L expression might be increased in TH2-like asthma and that expression levels would be associated with single nucleotide polymorphisms in IL1RL1, possibly explaining its genetic relationship with asthma. We also sought to evaluate the regulation of ST2L and sST2 in vitro.
  
  
  METHODS
  Endobronchial brushings and biopsies were obtained and expression of ST2L compared by severity levels, as well as by TH2-like biomarkers. Subjects were genotyped and the relationship of dichotomous expression of ST2L and sST2 to single nucleotide polymorphisms in IL1RL1 were determined. Epithelial cells were grown in air-liquid interface culture, and ST2L and sST2 responses to IFN-γ and IL-13 were evaluated.
  
  
  RESULTS
  ST2L expression was increased in severe asthma (P = .02) and associated with multiple indicators of TH2-like inflammation, including blood eosinophils (P = .001), exhaled nitric oxide (P = .003), and epithelial CLCA1 (P < .0001) and eotaxin-3 (P = .001) mRNA expression. Multiple single nucleotide polymorphisms in IL1RL1 were found in relation to dichotomous expression of both ST2L and sST2. sST2 expression was associated with IFN-γ expression in bronchoalveolar lavage, while inducing its expression in vitro in primary human epithelial cells.
  
  
  CONCLUSIONS
  Both pathologic and genetic approaches support a role for IL1RL1 in severe asthma, as well as TH2-lke asthma, suggesting that targeting this pathway may have therapeutic benefits.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pa. Electronic address: traisterrs@upmc.edu.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Traister
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Crystal E
authors.initials: CE
authors.lastname: Uvalle
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pa.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
mesh_terms: D000328:Adult; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D055815:Young Adult
chemical_list: C120429:CCL26 protein, human; C492109:CLCA1 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D018118:Chloride Channels; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D009569:Nitric Oxide; D007371:Interferon-gamma
keywords: Asthma; IL1RL1; ST2L; T(H)2 inflammation; sST2; single nucleotide polymorphisms
references.citation: Am J Respir Crit Care Med. 2013 Aug 15;188(4):432-9
references.pmid: 23805875
references.citation: Clin Exp Immunol. 2012 Oct;170(1):1-9
references.pmid: 22943195
references.citation: Nat Genet. 2011 Jul 31;43(9):887-92
references.pmid: 21804549
references.citation: Cytokine. 2007 Dec;40(3):216-25
references.pmid: 18023358
references.citation: Am J Respir Crit Care Med. 2009 Sep 1;180(5):388-95
references.pmid: 19483109
references.citation: J Immunol. 2009 Oct 15;183(8):5094-103
references.pmid: 19801525
references.citation: J Immunol. 2010 Nov 15;185(10):5743-50
references.pmid: 20926795
references.citation: Am J Respir Crit Care Med. 2000 Dec;162(6):2341-51
references.pmid: 11112161
references.citation: Eur J Biochem. 1999 Sep;264(2):397-406
references.pmid: 10491084
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 23;108(34):14246-51
references.pmid: 21831839
references.citation: Immunity. 2005 Nov;23(5):479-90
references.pmid: 16286016
references.citation: J Biol Chem. 2007 Sep 7;282(36):26369-80
references.pmid: 17623648
references.citation: Nat Immunol. 2011 Sep 11;12(11):1055-62
references.pmid: 21909091
references.citation: J Allergy Clin Immunol. 2011 Jun;127(6):1457-65
references.pmid: 21397937
references.citation: J Immunol. 2009 Nov 15;183(10):6469-77
references.pmid: 19841166
references.citation: Lab Invest. 2008 Nov;88(11):1245-53
references.pmid: 18762778
references.citation: J Allergy Clin Immunol. 2010 Mar;125(3):752-4
references.pmid: 20153038
references.citation: J Allergy Clin Immunol. 2014 Feb;133(2):388-94
references.pmid: 24075231
references.citation: J Allergy Clin Immunol. 2007 Nov;120(5 Suppl):S94-138
references.pmid: 17983880
references.citation: J Allergy Clin Immunol. 2013 Mar;131(3):856-65
references.pmid: 23380221
references.citation: Mucosal Immunol. 2014 Sep;7(5):1175-85
references.pmid: 24518246
references.citation: Clin Exp Allergy. 2012 May;42(5):760-8
references.pmid: 22092728
references.citation: Nat Genet. 2009 Mar;41(3):342-7
references.pmid: 19198610
references.citation: Int Arch Allergy Immunol. 2011;155 Suppl 1:12-20
references.pmid: 21646790
references.citation: J Allergy Clin Immunol. 2008 Jun;121(6):1484-90
references.pmid: 18539196
references.citation: Am J Respir Crit Care Med. 1999 Sep;160(3):1001-8
references.pmid: 10471631
references.citation: J Clin Invest. 2013 Oct;123(10):4208-18
references.pmid: 23999434