Kobayashi, M. et al. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. J. Clin. Invest. 111, 1297-1308

Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/2003; 111(9):1297-308. DOI: 10.1172/JCI17085
Source: PubMed


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.

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    • "These broadly protective roles for gut TLR and inflammasome signals in acute intestinal inflammation contrast starkly with pathogenic roles played by these signals in the Il10−/−or Helicobacter hepaticus–induced chronic colitis models. MyD88 signaling promotes spontaneous colitis in both Il10−/−mice and LysMStat3KO mice; the latter mice are rendered hyporesponsive to IL-10 by a myeloid cell–specific deletion of Stat3 (Kobayashi et al., 2003; Rakoff-Nahoum et al., 2006). Moreover, we have recently shown that colitis induced by H. hepaticus colonization of RAG−/− mice requires MyD88 expression by hematopoietic cells (Asquith et al., 2010). "
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    ABSTRACT: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses to the intestinal microbiota, and by chronic intestinal inflammation. Several recent studies demonstrate the importance of innate microbial recognition by immune and nonimmune cells in the gut. Paradoxically, either diminished or exacerbated innate immune signaling may trigger the breakdown of intestinal homeostasis, leading to IBD and colitis-associated cancer (CAC). This dichotomy may reflect divergent functional roles for immune sensing in intestinal epithelial cells and leukocytes, which may vary with distinct disease mechanisms.
    Journal of Experimental Medicine 08/2010; 207(8):1573-7. DOI:10.1084/jem.20101330 · 12.52 Impact Factor
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    • "In contrast, increased TLR4-induced PPARγ activity results in subsequent uncoupling of NF-κB target genes as a part of a negative feedback mechanism and therefore limits inflammation [51] [52]. Studies in mice support the hypothesis that TLR4 mutations elevate the receptor function and promote intestinal inflammation via excessively activated cytokine-secretion [53] [54], possibly due to an increased activity of the receptor in response to physiological LPS concentrations. Additionally, mutations within the TLR4 gene locus can also lead to a functional loss of TLR4 that worsens DSS-induced colitis in mice by disturbing the intestinal homeostasis and barrier function [47] [53]. "
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    ABSTRACT: Recent years have raised evidence that the intestinal microbiota plays a crucial role in the pathogenesis of chronic inflammatory bowels diseases. This evidence comes from several observations. First, animals raised under germ-free conditions do not develop intestinal inflammation in several different model systems. Second, antibiotics are able to modulate the course of experimental colitis. Third, genetic polymorphisms in a variety of genes of the innate immune system have been associated with chronic intestinal inflammatory diseases. Dysfunction of these molecules results in an inappropriate response to bacterial and antigenic stimulation of the innate immune system in the gastrointestinal tract. Variants of pattern recognition receptors such as NOD2 or TLRs by which commensal and pathogenic bacteria can be detected have been shown to be involved in the pathogenesis of IBD. But not only pathways of microbial detection but also intracellular ways of bacterial processing such as autophagosome function are associated with the risk to develop Crohn's disease. Thus, the "environment concept" and the "genetic concept" of inflammatory bowel disease pathophysiology are converging via the intestinal microbiota and the recognition mechanisms for an invasion of members of the microbiota into the mucosa.
    06/2010; 2010(6):671258. DOI:10.4061/2010/671258
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    • "Myeloid cell-specific deletion of STAT3 results in development of spontaneous enterocolitis in mice.173 Strikingly, crossing myeloid cell-specific STAT3-deficient mice with TLR4-knockout attenuates intestinal inflammation,174 implying that disruption of STAT3 expression leads to overly activated innate immune responses via TLR4 toward the resident microflora and interferes with the adaptive immune system by inhibiting induction of antigen-specific T-cell tolerance in the intestinal mucosa. In return, defective T-cell apoptosis may subvert signaling of, e.g., TLR5/9 (or other PRRs), further mobilizing the effector function of TH1 cells, leading to enhanced IFNγ and IL-12/IL-23 production and excessive cell proliferation, which aggravates and sustains injurious immunologic reactions in the inflamed intestine. "
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    ABSTRACT: Differential alteration of Toll-like receptor (TLR) expression in inflammatory bowel disease (IBD) was first described 10 years ago. Since then, studies from many groups have led to the current concept that TLRs represent key mediators of innate host defense in the intestine, involved in maintaining mucosal as well as commensal homeostasis. Recent findings in diverse murine models of colitis have helped to reveal the mechanistic importance of TLR dysfunction in IBD pathogenesis. It has become evident that environment, genetics, and host immunity form a multidimensional and highly interactive regulatory triad that controls TLR function in the intestinal mucosa. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes in IBD colitis and associated cancer.
    Inflammatory Bowel Diseases 04/2010; 16(9):1583-97. DOI:10.1002/ibd.21282 · 4.46 Impact Factor
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