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

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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 languageEnglish
Pages (from-to)456-467
Number of pages12
JournalGastroenterology
Volume149
Issue number2
Early online date25 Apr 2015
DOIs
Publication statusPublished - Aug 2015

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Interleukin-6
Lymphocytes
Cytokines
Inflammation
Colon
Interleukin-7 Receptors
Colitis
Inflammatory Bowel Diseases
Interferons
Bacterial DNA
CD4 Antigens
Antibodies
Organ Culture Techniques
Intraperitoneal Injections
Histology
Flow Cytometry
Cell Culture Techniques
Enzyme-Linked Immunosorbent Assay

Keywords

  • UC
  • CD
  • innate immunity
  • immune regulation

Cite this

Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation. / Powell, Nick; Lo, Jonathan W; Biancheri, Paolo; Vossenkämper, Anna; Pantazi, Eirini; Walker, Alan W; Stolarczyk, Emilie; Ammoscato, Francesca; Goldberg, Rimma; Scott, Paul; Canavan, James B; Perucha, Esperanza; Garrido-Mesa, Natividad; Irving, Peter M; Sanderson, Jeremy D; Hayee, Bu; Howard, Jane K; Parkhill, Julian; MacDonald, Thomas T; Lord, Graham M.

In: Gastroenterology, Vol. 149, No. 2, 08.2015, p. 456-467.

Research output: Contribution to journalArticle

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
Powell, Nick ; Lo, Jonathan W ; Biancheri, Paolo ; Vossenkämper, Anna ; Pantazi, Eirini ; Walker, Alan W ; Stolarczyk, Emilie ; Ammoscato, Francesca ; Goldberg, Rimma ; Scott, Paul ; Canavan, James B ; Perucha, Esperanza ; Garrido-Mesa, Natividad ; Irving, Peter M ; Sanderson, Jeremy D ; Hayee, Bu ; Howard, Jane K ; Parkhill, Julian ; MacDonald, Thomas T ; Lord, Graham M. / Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation. In: Gastroenterology. 2015 ; Vol. 149, No. 2. pp. 456-467.
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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.",
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note = "Date of Acceptance: 25/04/2015 Copyright {\circledC} 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.",
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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

VL - 149

SP - 456

EP - 467

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -