Interleukin-15 expression is increased in human eosinophilic esophagitis and mediates pathogenesis in mice.
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.
Zhu
Xiang
X
Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
Wang
Meiqin
M
Mavi
Parm
P
Rayapudi
Madhavi
M
Pandey
Akhilesh K
AK
Kaul
Ajay
A
Putnam
Philip E
PE
Rothenberg
Marc E
ME
Mishra
Anil
A
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
D019409:Interleukin-15; D053647:Receptors, Interleukin-15
J Clin Invest. 1999 Jun;103(12):1719-27
10377178
Eur J Immunol. 1997 Oct;27(10):2737-40
9368634
J Allergy Clin Immunol. 2001 Dec;108(6):891-4
11742263
Immunol Lett. 2003 Jan 22;85(2):131-4
12527218
Inflamm Res. 1998 Jul;47(7):285-9
9719492
Eur J Immunol. 1998 Jul;28(7):2152-8
9692884
Gastroenterology. 2005 Sep;129(3):985-94
16143136
J Clin Invest. 2006 Feb;116(2):536-47
16453027
Curr Opin Immunol. 2005 Dec;17(6):595-600
16214317
J Leukoc Biol. 2007 Apr;81(4):916-24
17194734
Science. 1994 May 13;264(5161):965-8
8178155
J Immunol. 2008 Jun 15;180(12):7958-68
18523259
J Exp Med. 1995 Oct 1;182(4):1169-74
7561691
J Clin Invest. 2001 Jan;107(1):83-90
11134183
Gastroenterology. 1995 Nov;109(5):1503-12
7557132
Immunol Res. 1995;14(1):1-12
7561338
Immunity. 2003 Nov;19(5):739-48
14614860
J Pediatr Gastroenterol Nutr. 2009 Feb;48(2):152-60
19179876
J Immunol. 2010 Apr 1;184(7):4033-41
20208004
Blood. 2001 Apr 15;97(8):2358-65
11290598
Mol Immunol. 2002 May;38(12-13):887-90
12009565
J Immunol. 2002 Mar 1;168(5):2464-9
11859139
J Allergy Clin Immunol. 2006 Nov;118(5):1054-9
17088129
Gastrointest Endosc. 2005 Jun;61(7):795-801
15933677
Nat Rev Immunol. 2003 Mar;3(3):211-22
12658269
Immunity. 2007 Apr;26(4):503-17
17398124
J Exp Med. 2000 Mar 6;191(5):771-80
10704459
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4935-9
8197160
Gastroenterology. 2002 May;122(5):1216-25
11984507
J Immunol. 2003 Dec 1;171(11):5853-64
14634095
Gastroenterology. 2003 Nov;125(5):1419-27
14598258
Science. 1999 Jan 8;283(5399):222-5
9880255
J Pediatr Gastroenterol Nutr. 2007 Jul;45(1):22-31
17592361
Immunol Allergy Clin North Am. 2009 Feb;29(1):29-40, viii
19141339
Pediatr Dev Pathol. 2004 Jan-Feb;7(1):5-16
15255030
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6273-8
9600955
J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):20-6
17204948
Am J Physiol Gastrointest Liver Physiol. 2009 Sep;297(3):G550-8
19571233
Immunity. 2004 Sep;21(3):367-77
15357948
J Immunol. 2007 Sep 15;179(6):3452-62
17785779
Immunity. 2004 Sep;21(3):357-66
15357947
Curr Mol Med. 2002 Jun;2(4):371-80
12108948