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

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Print ISSN: 0021-9738 (Print) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
      Drosophila Proteins* ; Repressor Proteins* ; Transcription Factors*; DNA-Binding Proteins/*metabolism ; Enterocolitis/*metabolism ; Interleukin-12/*metabolism ; Membrane Glycoproteins/*metabolism ; Myeloid Cells/*physiology ; Protein Subunits/*metabolism ; Receptors, Cell Surface/*metabolism ; Trans-Activators/*metabolism; Animals ; Chronic Disease ; DNA-Binding Proteins/genetics ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Enterocolitis/pathology ; Interferon-gamma/metabolism ; Interleukin-10/metabolism ; Interleukin-12/genetics ; Interleukin-12 Subunit p40 ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells/cytology ; Protein Subunits/genetics ; Proteins/metabolism ; 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 ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism
    • 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.
    • Comments:
      Comment in: J Clin Invest. 2003 May;111(9):1284-6. (PMID: 12727919)
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    • Accession Number:
      0 (DNA-Binding Proteins)
      0 (Drosophila Proteins)
      0 (Interleukin-12 Subunit p40)
      0 (Lipopolysaccharides)
      0 (Membrane Glycoproteins)
      0 (Protein Subunits)
      0 (Proteins)
      0 (Rag2 protein, mouse)
      0 (Receptors, Cell Surface)
      0 (Repressor Proteins)
      0 (SOCS3 protein, human)
      0 (STAT1 Transcription Factor)
      0 (STAT3 Transcription Factor)
      0 (Socs3 protein, mouse)
      0 (Stat1 protein, mouse)
      0 (Stat3 protein, mouse)
      0 (Suppressor of Cytokine Signaling 3 Protein)
      0 (Suppressor of Cytokine Signaling Proteins)
      0 (Toll-Like Receptor 4)
      0 (Toll-Like Receptors)
      0 (Trans-Activators)
      0 (Transcription Factors)
      0 (Tumor Necrosis Factor-alpha)
      0 (V(D)J recombination activating protein 2)
      130068-27-8 (Interleukin-10)
      187348-17-0 (Interleukin-12)
      82115-62-6 (Interferon-gamma)
    • Publication Date:
      Date Created: 20030503 Date Completed: 20030605 Latest Revision: 20201219
    • Publication Date:
      20221213
    • Accession Number:
      PMC154445
    • Accession Number:
      10.1172/JCI17085
    • Accession Number:
      12727921