Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice

J Clin Invest. 2003 May;111(9):1297-308. doi: 10.1172/JCI17085.

Abstract

Stat3 plays an essential role in IL-10 signaling pathways. A myeloid cell-specific deletion of Stat3 resulted in inflammatory cytokine production and development of chronic enterocolitis with enhanced Th1 responses in mice. In this study, we analyzed the mechanism by which a Stat3 deficiency in myeloid cells led to the induction of chronic enterocolitis in vivo. Even in the absence of Stat1, which is essential for IFN-gamma signaling pathways, Stat3 mutant mice developed chronic enterocolitis. TNF-alpha/Stat3 double-mutant mice developed severe chronic enterocolitis with enhanced Th1 cell development. IL-12p40/Stat3 double-mutant mice, however, showed normal Th1 responses and no inflammatory change in the colon. RAG2/Stat3 double-mutant mice did not develop enterocolitis, either. These findings indicate that overproduction of IL-12p40, which induces potent Th1 responses, is essential for the development of chronic enterocolitis in Stat3 mutant mice. Furthermore, enterocolitis was significantly improved and IFN-gamma production by T cells was reduced in TLR4/Stat3 double-mutant mice, indicating that TLR4-mediated recognition of microbial components triggers aberrant IL-12p40 production by myeloid cells, leading to the development of enterocolitis. Thus, this study clearly established a sequential innate and acquired immune mechanism for the development of Th1-dependent enterocolitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Drosophila Proteins*
  • Enterocolitis / metabolism*
  • Enterocolitis / pathology
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism*
  • Interleukin-12 Subunit p40
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / cytology
  • Myeloid Cells / physiology*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Proteins / metabolism
  • Receptors, Cell Surface / metabolism*
  • Repressor Proteins*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Spleen / cytology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Interleukin-12 Subunit p40
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Protein Subunits
  • Proteins
  • Rag2 protein, mouse
  • Receptors, Cell Surface
  • Repressor Proteins
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Trans-Activators
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • V(D)J recombination activating protein 2
  • Interleukin-10
  • Interleukin-12
  • Interferon-gamma