Interleukin 17, Produced by γδ T Cells, Contributes to Hepatic Inflammation in a Mouse Model of Biliary Atresia and Is Increased in Livers of Patients
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Interleukin 17, Produced by γδ T Cells, Contributes to Hepatic Inflammation in a Mouse Model of Biliary Atresia and Is Increased in Livers of Patients. / Klemann, Christian; Schröder, Arne; Dreier, Anika; Möhn, Nora; Dippel, Stephanie; Winterberg, Thomas; Wilde, Anne; Yu, Yi; Thorenz, Anja; Gueler, Faikah; Jörns, Anne; Tolosa, Eva; Leonhardt, Johannes; Haas, Jan D; Prinz, Immo; Vieten, Gertrud; Petersen, Claus; Kuebler, Joachim F.
In: GASTROENTEROLOGY, Vol. 150, No. 1, 01.2016, p. 229-241.e5.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Interleukin 17, Produced by γδ T Cells, Contributes to Hepatic Inflammation in a Mouse Model of Biliary Atresia and Is Increased in Livers of Patients
AU - Klemann, Christian
AU - Schröder, Arne
AU - Dreier, Anika
AU - Möhn, Nora
AU - Dippel, Stephanie
AU - Winterberg, Thomas
AU - Wilde, Anne
AU - Yu, Yi
AU - Thorenz, Anja
AU - Gueler, Faikah
AU - Jörns, Anne
AU - Tolosa, Eva
AU - Leonhardt, Johannes
AU - Haas, Jan D
AU - Prinz, Immo
AU - Vieten, Gertrud
AU - Petersen, Claus
AU - Kuebler, Joachim F
N1 - Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2016/1
Y1 - 2016/1
N2 - BACKGROUND & AIMS: Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA.METHODS: We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control).RESULTS: Livers from rhesus rota virus-infected mice with BA had 7-fold more Il17a messenger RNA than control mice (P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 μmol/L vs 78 μmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues (P = .02).CONCLUSIONS: In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target.
AB - BACKGROUND & AIMS: Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA.METHODS: We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control).RESULTS: Livers from rhesus rota virus-infected mice with BA had 7-fold more Il17a messenger RNA than control mice (P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 μmol/L vs 78 μmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues (P = .02).CONCLUSIONS: In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target.
KW - Animals
KW - Biliary Atresia
KW - Cells, Cultured
KW - Cytokines
KW - Disease Models, Animal
KW - Disease Progression
KW - Female
KW - Hepatitis
KW - Humans
KW - Immunohistochemistry
KW - Infant
KW - Interleukin-17
KW - Liver
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - RNA, Messenger
KW - Random Allocation
KW - Real-Time Polymerase Chain Reaction
KW - Statistics, Nonparametric
KW - T-Lymphocytes
KW - Up-Regulation
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1053/j.gastro.2015.09.008
DO - 10.1053/j.gastro.2015.09.008
M3 - SCORING: Journal article
C2 - 26404950
VL - 150
SP - 229-241.e5
JO - GASTROENTEROLOGY
JF - GASTROENTEROLOGY
SN - 0016-5085
IS - 1
ER -