Interleukin 6 Increases Production of Cytokines by Colonic Innate Lymphoid Cells in Mice and Patients With Chronic Intestinal Inflammation.
OBJECTIVE
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 (IBD); 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 IBD patients, also increased the production of IL17A, IL22, and interferon-γ by cultured human colon CD3-negative, IL7-receptor-positive cells.
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; Gastroenterology Department, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Nick
N
Powell
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Jonathan W
JW
Lo
Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Paolo
P
Biancheri
Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Anna
A
Vossenkämper
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Eirini
E
Pantazi
Pathogen Genomics Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridgeshire, United Kingdom; Microbiology Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom.
Alan W
AW
Walker
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom; Division of Diabetes and Nutritional Sciences, King's College London, London, United Kingdom.
Emilie
E
Stolarczyk
Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Francesca
F
Ammoscato
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; Gastroenterology Department, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Rimma
R
Goldberg
Pathogen Genomics Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridgeshire, United Kingdom.
Paul
P
Scott
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
James B
JB
Canavan
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Esperanza
E
Perucha
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Natividad
N
Garrido-Mesa
Gastroenterology Department, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Peter M
PM
Irving
Gastroenterology Department, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom.
Jeremy D
JD
Sanderson
Gastroenterology Department, Kings College Hospital, London, United Kingdom.
Bu
B
Hayee
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom; Division of Diabetes and Nutritional Sciences, King's College London, London, United Kingdom.
Jane K
JK
Howard
Pathogen Genomics Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridgeshire, United Kingdom.
Julian
J
Parkhill
Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Thomas T
TT
MacDonald
Department of Experimental Immunobiology, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, United Kingdom; National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom. Electronic address: graham.lord@kcl.ac.uk.
Graham M
GM
Lord
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism*; D018929:Cell Culture Techniques; D003106:Colon / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D007378:Interleukins / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055636:Receptors, Natural Cytotoxicity Triggering / Q000378:metabolism; D000097043:Interleukin-22
D017252:CD3 Complex; D015704:CD4 Antigens; D016207:Cytokines; D007371:Interferon-gamma; D020381:Interleukin-17; D053582:Interleukin-1alpha; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D055636:Receptors, Natural Cytotoxicity Triggering; D000097043:Interleukin-22; C508717:IL17A protein, human
CD; Immune Regulation; Innate Immunity; UC