Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation

Nick Powell; Jonathan W Lo; Paolo Biancheri; Anna Vossenkämper; Eirini Pantazi; Alan W Walker; Emilie Stolarczyk; Francesca Ammoscato; Rimma Goldberg; Paul Scott; James B Canavan; Esperanza Perucha; Natividad Garrido-Mesa; Peter M Irving; Jeremy D Sanderson; Bu Hayee; Jane K Howard; Julian Parkhill; Thomas T MacDonald; Graham M Lord

doi:10.1053/j.gastro.2015.04.017

Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation

Nick Powell, Jonathan W Lo, Paolo Biancheri, Anna Vossenkämper, Eirini Pantazi, Alan W Walker, Emilie Stolarczyk, Francesca Ammoscato, Rimma Goldberg, Paul Scott, James B Canavan, Esperanza Perucha, Natividad Garrido-Mesa, Peter M Irving, Jeremy D Sanderson, Bu Hayee, Jane K Howard, Julian Parkhill, Thomas T MacDonald, Graham M Lord

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

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Abstract

BACKGROUND & AIMS: Innate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation.

METHODS: ILCs were isolated from colons of Tbx21(-/-) × Rag2(-/-) mice (TRUC), which develop colitis; patients with inflammatory bowel disease; and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota.

RESULTS: IL17A- and IL22-producing, natural cytotoxicity receptor-negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1α induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon-γ by human intestinal CD3-negative, IL7-receptor-positive cells, in a dose-dependent manner.

CONCLUSIONS: IL6 contributes to activation of colonic natural cytotoxicity receptor-negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1α-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some inflammatory bowel disease patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor-positive cells.

Original language	English
Pages (from-to)	456-467
Number of pages	12
Journal	Gastroenterology
Volume	149
Issue number	2
Early online date	25 Apr 2015
DOIs	https://doi.org/10.1053/j.gastro.2015.04.017
Publication status	Published - Aug 2015

Bibliographical note

Date of Acceptance: 25/04/2015
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Acknowledgments

The authors are grateful to the Wellcome Trust Sanger Institute’s core sequencing team for performing 16S ribosomal RNA gene sequencing, and to Chris Evagora and support staff at the Pathology Core at Queen Mary University of London.
Microbiota sequence data were deposited in the European Nucleotide Archive under Study Accession Number ERP005850 and Sample Accession Numbers ERS459682–ERS459702.

Keywords

UC
CD
innate immunity
immune regulation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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IL6_InnateLymphoidCells_Gastroenterology2015
Open Access funded by Wellcome Trust This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
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Cite this

Powell, N., Lo, J. W., Biancheri, P., Vossenkämper, A., Pantazi, E., Walker, A. W., Stolarczyk, E., Ammoscato, F., Goldberg, R., Scott, P., Canavan, J. B., Perucha, E., Garrido-Mesa, N., Irving, P. M., Sanderson, J. D., Hayee, B., Howard, J. K., Parkhill, J., MacDonald, T. T., & Lord, G. M. (2015). Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation. Gastroenterology, 149(2), 456-467. https://doi.org/10.1053/j.gastro.2015.04.017

Powell, N, Lo, JW, Biancheri, P, Vossenkämper, A, Pantazi, E, Walker, AW, Stolarczyk, E, Ammoscato, F, Goldberg, R, Scott, P, Canavan, JB, Perucha, E, Garrido-Mesa, N, Irving, PM, Sanderson, JD, Hayee, B, Howard, JK, Parkhill, J, MacDonald, TT & Lord, GM 2015, 'Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation', Gastroenterology, vol. 149, no. 2, pp. 456-467. https://doi.org/10.1053/j.gastro.2015.04.017

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title = "Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation",

abstract = "BACKGROUND & AIMS: Innate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation.METHODS: ILCs were isolated from colons of Tbx21(-/-) × Rag2(-/-) mice (TRUC), which develop colitis; patients with inflammatory bowel disease; and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota.RESULTS: IL17A- and IL22-producing, natural cytotoxicity receptor-negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1α induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon-γ by human intestinal CD3-negative, IL7-receptor-positive cells, in a dose-dependent manner.CONCLUSIONS: IL6 contributes to activation of colonic natural cytotoxicity receptor-negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1α-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some inflammatory bowel disease patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor-positive cells.",

keywords = "UC, CD, innate immunity, immune regulation",

author = "Nick Powell and Lo, {Jonathan W} and Paolo Biancheri and Anna Vossenk{\"a}mper and Eirini Pantazi and Walker, {Alan W} and Emilie Stolarczyk and Francesca Ammoscato and Rimma Goldberg and Paul Scott and Canavan, {James B} and Esperanza Perucha and Natividad Garrido-Mesa and Irving, {Peter M} and Sanderson, {Jeremy D} and Bu Hayee and Howard, {Jane K} and Julian Parkhill and MacDonald, {Thomas T} and Lord, {Graham M}",

note = "Date of Acceptance: 25/04/2015 Copyright {\textcopyright} 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. Acknowledgments The authors are grateful to the Wellcome Trust Sanger Institute{\textquoteright}s core sequencing team for performing 16S ribosomal RNA gene sequencing, and to Chris Evagora and support staff at the Pathology Core at Queen Mary University of London. Microbiota sequence data were deposited in the European Nucleotide Archive under Study Accession Number ERP005850 and Sample Accession Numbers ERS459682–ERS459702.",

year = "2015",

month = aug,

doi = "10.1053/j.gastro.2015.04.017",

language = "English",

volume = "149",

pages = "456--467",

journal = "Gastroenterology",

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TY - JOUR

T1 - Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation

AU - Powell, Nick

AU - Lo, Jonathan W

AU - Biancheri, Paolo

AU - Vossenkämper, Anna

AU - Pantazi, Eirini

AU - Walker, Alan W

AU - Stolarczyk, Emilie

AU - Ammoscato, Francesca

AU - Goldberg, Rimma

AU - Scott, Paul

AU - Canavan, James B

AU - Perucha, Esperanza

AU - Garrido-Mesa, Natividad

AU - Irving, Peter M

AU - Sanderson, Jeremy D

AU - Hayee, Bu

AU - Howard, Jane K

AU - Parkhill, Julian

AU - MacDonald, Thomas T

AU - Lord, Graham M

N1 - Date of Acceptance: 25/04/2015 Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved. Acknowledgments The authors are grateful to the Wellcome Trust Sanger Institute’s core sequencing team for performing 16S ribosomal RNA gene sequencing, and to Chris Evagora and support staff at the Pathology Core at Queen Mary University of London. Microbiota sequence data were deposited in the European Nucleotide Archive under Study Accession Number ERP005850 and Sample Accession Numbers ERS459682–ERS459702.

PY - 2015/8

Y1 - 2015/8

N2 - BACKGROUND & AIMS: Innate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation.METHODS: ILCs were isolated from colons of Tbx21(-/-) × Rag2(-/-) mice (TRUC), which develop colitis; patients with inflammatory bowel disease; and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota.RESULTS: IL17A- and IL22-producing, natural cytotoxicity receptor-negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1α induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon-γ by human intestinal CD3-negative, IL7-receptor-positive cells, in a dose-dependent manner.CONCLUSIONS: IL6 contributes to activation of colonic natural cytotoxicity receptor-negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1α-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some inflammatory bowel disease patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor-positive cells.

AB - BACKGROUND & AIMS: Innate lymphoid cells (ILCs) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and in human beings with chronic intestinal inflammation.METHODS: ILCs were isolated from colons of Tbx21(-/-) × Rag2(-/-) mice (TRUC), which develop colitis; patients with inflammatory bowel disease; and patients without colon inflammation (controls). ILCs were characterized by flow cytometry; cytokine production was measured by enzyme-linked immunosorbent assay and cytokine bead arrays. Mice were given intraperitoneal injections of depleting (CD4, CD90), neutralizing (IL6), or control antibodies. Isolated colon tissues were analyzed by histology, explant organ culture, and cell culture. Bacterial DNA was extracted from mouse fecal samples to assess the intestinal microbiota.RESULTS: IL17A- and IL22-producing, natural cytotoxicity receptor-negative, ILC3 were the major subset of ILCs detected in colons of TRUC mice. Combinations of IL23 and IL1α induced production of cytokines by these cells, which increased further after administration of IL6. Antibodies against IL6 reduced colitis in TRUC mice without significantly affecting the structure of their intestinal microbiota. Addition of IL6 increased production of IL17A, IL22, and interferon-γ by human intestinal CD3-negative, IL7-receptor-positive cells, in a dose-dependent manner.CONCLUSIONS: IL6 contributes to activation of colonic natural cytotoxicity receptor-negative, CD4-negative, ILC3s in mice with chronic intestinal inflammation (TRUC mice) by increasing IL23- and IL1α-induced production of IL17A and IL22. This pathway might be targeted to treat patients with IBD because IL6, which is highly produced in colonic tissue by some inflammatory bowel disease patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor-positive cells.

KW - UC

KW - CD

KW - innate immunity

KW - immune regulation

U2 - 10.1053/j.gastro.2015.04.017

DO - 10.1053/j.gastro.2015.04.017

M3 - Article

C2 - 25917784

SN - 0016-5085

VL - 149

SP - 456

EP - 467

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation

Abstract

Bibliographical note

Keywords

UN SDGs

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