Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice.
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.
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Masaya
M
Kobayashi
Mi-Na
MN
Kweon
Hirotaka
H
Kuwata
Robert D
RD
Schreiber
Hiroshi
H
Kiyono
Kiyoshi
K
Takeda
Shizuo
S
Akira
D000818:Animals; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D029721:Drosophila Proteins; D004760:Enterocolitis / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000502:physiology*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013154:Spleen / Q000166:cytology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D011506:Proteins; C499308:Rag2 protein, mouse; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C064655:V(D)J recombination activating protein 2; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma