STAT4 Activation by Leukemia Inhibitory Factor Confers a Therapeutic Effect on Intestinal Inflammation

EMBO J. 2019 Mar 15;38(6):e99595. doi: 10.15252/embj.201899595. Epub 2019 Feb 15.

Abstract

T helper 17 (Th17)-cell differentiation triggered by interleukin-6 (IL-6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL-6 family cytokine, restricts inflammation by blocking Th17-cell differentiation via an unknown mechanism. Here, we report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical "AGG" elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il17a/Il17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, serves as a potential therapy for IBD.

Keywords: LIF; STAT4; Th17‐cell differentiation; intestinal inflammation; intestinal repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / prevention & control*
  • Gene Expression Regulation / drug effects*
  • Inflammation / chemically induced
  • Inflammation / immunology
  • Inflammation / prevention & control*
  • Interleukin-17 / immunology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Leukemia Inhibitory Factor / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • STAT4 Transcription Factor / physiology*
  • Signal Transduction
  • Th17 Cells / immunology

Substances

  • Il17a protein, mouse
  • Interleukin-17
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • STAT3 Transcription Factor
  • STAT4 Transcription Factor
  • Stat3 protein, mouse
  • Stat4 protein, mouse