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

Gastroenterology. 2015 Aug;149(2):456-67.e15. doi: 10.1053/j.gastro.2015.04.017. Epub 2015 Apr 25.

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 (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.

Keywords: CD; Immune Regulation; Innate Immunity; UC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • CD4 Antigens / metabolism*
  • Cell Culture Techniques
  • Colon / cytology
  • Colon / immunology
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Immunity, Innate / drug effects*
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / immunology*
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-1alpha / metabolism
  • Interleukin-23 / metabolism
  • Interleukin-6 / administration & dosage
  • Interleukin-6 / pharmacology*
  • Interleukins / metabolism
  • Lymphocytes / drug effects*
  • Lymphocytes / immunology
  • Mice
  • Mice, Knockout
  • Receptors, Natural Cytotoxicity Triggering / metabolism

Substances

  • CD3 Complex
  • CD4 Antigens
  • Cytokines
  • IL17A protein, human
  • Interleukin-17
  • Interleukin-1alpha
  • Interleukin-23
  • Interleukin-6
  • Interleukins
  • Receptors, Natural Cytotoxicity Triggering
  • Interferon-gamma
  • interleukin-22