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 - Note: This work was supported by the Wellcome Trust [grant numbers: WT101159AIA, WT088747MA, 091009 and 098051], Medical Research Council [grant numbers G0802068 and MR/K002996/1], Scottish Government Rural and Environmentak Science and Analysis Service, Institute for Health Research Biomedical Research Centre and King's College London.
PY - 2015/8/31
Y1 - 2015/8/31
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 (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-╬│ 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-╬│ 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 (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-╬│ 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-╬│ by cultured human colon CD3-negative, IL7-receptor-positive cells.
KW - Biological sciences
KW - CD
KW - UC
KW - immune regulation
KW - innate immunity
UR - https://pubmed.ncbi.nlm.nih.gov/25917784/
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 -