Intestinal-Specific TNFα Overexpression Induces Crohn’s-Like Ileitis in Mice (original) (raw)
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Proceedings of the National Academy of Sciences of the United States of America, 2011
TNF plays a crucial role in the pathogenesis of Crohn disease. Dysregulated TNF production in mice that bear the genetic deletion of the TNF AU-rich regulatory elements (ARE) (Tnf(ΔARE/+) mice) results in TNF receptor I (TNFRI)-dependent spontaneous Crohn-like pathology. Current concepts consider intestinal epithelial cell (IEC) responses to TNF to be critical for intestinal pathology, but the potential contribution of IEC-derived TNF in disease pathogenesis has not been addressed. In this study we examined whether IEC are sufficient as cellular targets or sources of TNF in the development of intestinal pathology. Using IEC-specific reactivation of a hypomorphic Tnf(ΔAREneo) allele in mice, we show that selective chronic overproduction of TNF by IEC suffices to cause full development of Crohn-like pathology. Epithelial TNF overexpression leads to early activation of the underlying intestinal myofibroblast, a cell type previously identified as a sufficient target of TNF for disease d...
Journal of Crohn's and Colitis, 2021
Background and Aims Crohn’s disease is a debilitating chronic inflammatory disorder of the mammalian gastrointestinal tract. Current interventions using anti-tumour necrosis factor [anti-TNF] biologics show long-term benefit in only half of patients. This study focused on the role of the TNF receptor 1 [TNFR1] in pathogenesis in a TNF-driven model of ileitis. Methods We studied TNFΔAU-rich element [ARE]/+ [TNFdARE] mice, which develop progressive ileitis similar to Crohn’s ileitis. Histopathological analysis and gene expression profiling were used to characterize disease progression from 5 to 16 weeks. Mice with TNFR1 hemizygosity [TNFdARE/R1het] allowed us to assess gene dosage effects. Transcriptional profiling established inflection points in disease progression; inflammatory gene expression increased at 8 weeks with a plateau by 10 weeks, so these were selected as endpoints of treatment using the TNF biologic infliximab and the TNFR1-specific XPro1595. Differences in recruitment...
Proceedings of the National Academy of Sciences of the United States of America, 2003
Tumor necrosis factor alpha (TNF-alpha) is an important mediator of programmed cell death, and TNF-alpha blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-alpha therapy in CD remains poorly understood. SAMP1/YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-alpha therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-alpha antibodies in human CD, a single injection of a chimeric anti-murine TNF-alpha antibody into SAMP1/YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell da...
Proceedings of the National Academy of Sciences, 2003
Tumor necrosis factor ␣ (TNF-␣) is an important mediator of programmed cell death, and TNF-␣ blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-␣ therapy in CD remains poorly understood. SAMP1͞YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-␣ therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-␣ antibodies in human CD, a single injection of a chimeric anti-murine TNF-␣ antibody into SAMP1͞YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-␣-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-␣ reduced membrane bound FAS͞CD95 expression in IEC from SAMP1͞YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-␣ therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.
Journal of Experimental Medicine, 2002
Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (TnfΔAREmouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon γ and requires the function of CD8+ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in...
Translational Research, 2017
Intestinal Subepithelial Myofibroblasts (SEMFs) exert a pro-fibrotic role in Crohn's disease (CD). TNFlike cytokine 1A (TL1A) and its receptors, death-domain receptor 3 (DR3) and decoy receptor 3 (DcR3) are mucosal factors with significant involvement in experimental inflammation and CD. We aimed to determine the regulation of expression of this system of proteins in SEMFs and intestinal epithelial cells. The relative amount of mRNA transcripts for TL1A, DR3 and DcR3 was measured by real-time RT-PCR in cultured primary SEMFs, colonic myofibroblast cell line 18CO and epithelial cell line HT29. Protein expression was determined by immunofluoresence. The effect of various pro-inflammatory stimuli in mRNA and protein expression was studied. TL1A mRNA and protein expression in primary SEMFs (and 18CO cells) was significantly upregulated after stimulation with IL-1α and/or TNF-α (32-44-fold increase, P<0.05 vs. unstimulated). Following stimulation with IL-1α+TNF-α+IFN-γ, HT-29 cells highly expressed DR3 (4.1-fold over unstimulated, P=0.008) and DcR3 (56-fold, P=0.009) and secreted soluble factors that led to induction of TL1A mRNA in primary SEMFs (28-fold, P=0.008). Activated epithelial cells significantly upregulated IL-8 expression in response to stimulation with recombinant TL1A. Supernatants from mucosal cultures of patients with CD were able to stimulate the expression of TL1A in cultured primary SEMFs, in comparison to supernatants from healthy controls (3.8-fold increase, P<0.05) or culture media alone (P<0.05). In conclusion, we found that pro-inflammatory cytokines are important regulators of the expression of TL1A in SEMFs and of its receptors in intestinal epithelial cells. Our results raise the possibility for involvement of TL1A/DR3/DR3 mediated mechanisms in epithelialmesenchymal interactions and the development of inflammation-induced intestinal fibrosis in CD.
Tumor Necrosis Factor’s Pathway in Crohn’s Disease: Potential for Intervention
International Journal of Molecular Sciences, 2021
Crohn’s disease (CD) is a chronic disorder characterized by full thickness patchy inflammation of the gastrointestinal tract. The pathogenesis is multifactorial and involves defective innate immune responses, microbiome alterations, and dysregulated activation of the acquired component of mucosal immunity. One of the molecular mediators that is involved at different levels in the initiation and progression of intestinal inflammation characteristic of CD is tumor necrosis factor (TNF). The present manuscript provides a comprehensive review focused on the potential role of TNF in the different phases of CD pathogenesis, particularly in light of its potential clinical implications. Currently available drugs blocking TNF are evaluated and discussed, specifically for open issues that still remain utilizing such therapy. TNF exerts a paramount role in the established phase of intestinal inflammation that characterizes CD patients, and anti-TNF biologics have definitely changed patient man...
Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn’s disease
Journal of Clinical Investigation, 2001
Introduction Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology that can occur in any part of the gastrointestinal tract, but most frequently in the small intestine (1). Although there is increasing evidence that genetic, immunologic, and environmental factors may be involved, the precise etiology and pathogenic mechanisms of disease remain unclear (1-5). Until recently, progress in understanding the pathogenesis of CD has been seriously hindered by a lack of animal models that faithfully resemble human disease. With the advent of new technologies, several animal models of IBD have recently been described (6-8). Most affect the large bowel rather than the small intestine and are artificially generated by immunologic, genetic, or chemical manipulation. Although these models have provided useful information concerning basic mechanisms of intestinal inflammation, they do not develop spontaneously and lack many of the important characteristics of CD (e.g., specific histological features, presence of ileitis, and maintenance of chronic inflammation). Therefore, these models may have limited value for investigating the precise etiopathogenesis of human CD (9). The SAMP1/Yit mouse is a unique model of intestinal inflammation. This model develops a spontaneous and chronic ileitis that closely resembles human CD in the absence of chemical, immunologic, or genetic manipulations (10). Here, we first describe the remarkable similarities between this model and human CD with regard to disease location and histological findings. Second, we report that Th1-type T cells from SAMP1/Yit mice can adoptively transfer disease. Last, we show that these pathogenic T cells directly mediate the resulting ileitis through a mechanism that may require TNF production. These findings demonstrate that pathogenic Th1-type T cells can mediate a Crohn'slike disease in a spontaneous mouse model of ileitis. Methods Animals. We have established a colony of SAMP1/Yit mice in a barrier facility at the University of Virginia from animals provided by S. Matsumoto (Yakult Central Institute for Microbiological Research, Tokyo, Japan). The SAMP1/Yit (H-2 k) mouse strain was originally derived from AKR mice (original parents purchased from The Jackson Laboratories, Bar Harbor,