title: Interleukin-15 expression is increased in human eosinophilic esophagitis and mediates pathogenesis in mice.
abstract: OBJECTIVE
  Quantitative microarray analyses have shown increased expression of interleukin-15 (IL-15) messenger RNA in the esophagus of patients with eosinophilic esophagitis (EoE), a recently recognized allergic disorder with poorly understood pathogenesis.
  
  
  METHODS
  Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses were performed to examine protein and transcript levels in tissue samples from patients with EoE. Tissues from IL-15Ra-deficient and wild-type (control) mice were also examined. Tissue eosinophilia was determined by immunostaining for major basic protein and flow cytometry for cell-surface receptors.
  
  
  RESULTS
  Quantitative polymerase chain reaction analyses showed that levels of IL-15 and its receptor IL-15Ra were increased approximately 6- and approximately 10-fold, respectively, in tissues from patients with EoE and approximately 3- and approximately 4-fold, respectively, in mice with allergen-induced EoE. A >2-fold increase in serum IL-15 protein levels was also detected in human EoE samples compared with those from healthy individuals. Human IL-15 messenger RNA levels correlated with esophageal eosinophilia (P < .001). IL-15Ra-deficient mice were protected from allergen-induced esophageal eosinophilia compared with controls (P < .001), even though similar levels of airway eosinophilia were observed in all mice. IL-15 activated STAT5 and CD4(+) T cells to produce cytokines that act on eosinophils. Incubation of primary esophageal epithelial cells from mice and humans with IL-15 caused a dose-dependent increase in the mRNA expression and protein levels of eotaxin-1, -2, and -3.
  
  
  CONCLUSIONS
  IL-15 mediates in the pathogenesis of EoE. IL-15 activates CD4(+) T cells to produce cytokines that act on eosinophils.
authors.affiliation: Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhu
authors.forename: Meiqin
authors.initials: M
authors.lastname: Wang
authors.forename: Parm
authors.initials: P
authors.lastname: Mavi
authors.forename: Madhavi
authors.initials: M
authors.lastname: Rayapudi
authors.forename: Akhilesh K
authors.initials: AK
authors.lastname: Pandey
authors.forename: Ajay
authors.initials: A
authors.lastname: Kaul
authors.forename: Philip E
authors.initials: PE
authors.lastname: Putnam
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Anil
authors.initials: A
authors.lastname: Mishra
mesh_terms: D000293:Adolescent; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D004802:Eosinophilia / Q000209:etiology*; D004941:Esophagitis / Q000209:etiology*; D005260:Female; D006801:Humans; D007223:Infant; D019409:Interleukin-15 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053647:Receptors, Interleukin-15 / Q000502:physiology
chemical_list: D019409:Interleukin-15; D053647:Receptors, Interleukin-15
references.citation: J Clin Invest. 1999 Jun;103(12):1719-27
references.pmid: 10377178
references.citation: Eur J Immunol. 1997 Oct;27(10):2737-40
references.pmid: 9368634
references.citation: J Allergy Clin Immunol. 2001 Dec;108(6):891-4
references.pmid: 11742263
references.citation: Immunol Lett. 2003 Jan 22;85(2):131-4
references.pmid: 12527218
references.citation: Inflamm Res. 1998 Jul;47(7):285-9
references.pmid: 9719492
references.citation: Eur J Immunol. 1998 Jul;28(7):2152-8
references.pmid: 9692884
references.citation: Gastroenterology. 2005 Sep;129(3):985-94
references.pmid: 16143136
references.citation: J Clin Invest. 2006 Feb;116(2):536-47
references.pmid: 16453027
references.citation: Curr Opin Immunol. 2005 Dec;17(6):595-600
references.pmid: 16214317
references.citation: J Leukoc Biol. 2007 Apr;81(4):916-24
references.pmid: 17194734
references.citation: Science. 1994 May 13;264(5161):965-8
references.pmid: 8178155
references.citation: J Immunol. 2008 Jun 15;180(12):7958-68
references.pmid: 18523259
references.citation: J Exp Med. 1995 Oct 1;182(4):1169-74
references.pmid: 7561691
references.citation: J Clin Invest. 2001 Jan;107(1):83-90
references.pmid: 11134183
references.citation: Gastroenterology. 1995 Nov;109(5):1503-12
references.pmid: 7557132
references.citation: Immunol Res. 1995;14(1):1-12
references.pmid: 7561338
references.citation: Immunity. 2003 Nov;19(5):739-48
references.pmid: 14614860
references.citation: J Pediatr Gastroenterol Nutr. 2009 Feb;48(2):152-60
references.pmid: 19179876
references.citation: J Immunol. 2010 Apr 1;184(7):4033-41
references.pmid: 20208004
references.citation: Blood. 2001 Apr 15;97(8):2358-65
references.pmid: 11290598
references.citation: Mol Immunol. 2002 May;38(12-13):887-90
references.pmid: 12009565
references.citation: J Immunol. 2002 Mar 1;168(5):2464-9
references.pmid: 11859139
references.citation: J Allergy Clin Immunol. 2006 Nov;118(5):1054-9
references.pmid: 17088129
references.citation: Gastrointest Endosc. 2005 Jun;61(7):795-801
references.pmid: 15933677
references.citation: Nat Rev Immunol. 2003 Mar;3(3):211-22
references.pmid: 12658269
references.citation: Immunity. 2007 Apr;26(4):503-17
references.pmid: 17398124
references.citation: J Exp Med. 2000 Mar 6;191(5):771-80
references.pmid: 10704459
references.citation: Proc Natl Acad Sci U S A. 1994 May 24;91(11):4935-9
references.pmid: 8197160
references.citation: Gastroenterology. 2002 May;122(5):1216-25
references.pmid: 11984507
references.citation: J Immunol. 2003 Dec 1;171(11):5853-64
references.pmid: 14634095
references.citation: Gastroenterology. 2003 Nov;125(5):1419-27
references.pmid: 14598258
references.citation: Science. 1999 Jan 8;283(5399):222-5
references.pmid: 9880255
references.citation: J Pediatr Gastroenterol Nutr. 2007 Jul;45(1):22-31
references.pmid: 17592361
references.citation: Immunol Allergy Clin North Am. 2009 Feb;29(1):29-40, viii
references.pmid: 19141339
references.citation: Pediatr Dev Pathol. 2004 Jan-Feb;7(1):5-16
references.pmid: 15255030
references.citation: Proc Natl Acad Sci U S A. 1998 May 26;95(11):6273-8
references.pmid: 9600955
references.citation: J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):20-6
references.pmid: 17204948
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Sep;297(3):G550-8
references.pmid: 19571233
references.citation: Immunity. 2004 Sep;21(3):367-77
references.pmid: 15357948
references.citation: J Immunol. 2007 Sep 15;179(6):3452-62
references.pmid: 17785779
references.citation: Immunity. 2004 Sep;21(3):357-66
references.pmid: 15357947
references.citation: Curr Mol Med. 2002 Jun;2(4):371-80
references.pmid: 12108948