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 (Tnf
Δ
AREmouse). 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 a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.
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 TnfΔAREneo 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 development in the Tnf ΔARE model. By contrast, restricted TNFRI expression on IEC although sufficient to confer IEC apoptosis after acute exogenous TNF administration, fails to induce pathology following chronic specific targeting of IEC by endogenous TNF in Tnf ΔARE/+ mice. Our results argue against IEC being early and sufficient responders to chronic TNF-mediated pathogenic signals and suggest that proinflammatory aberrations leading to chronic TNF production by IEC may initiate pathology in Crohn disease.inflammatory bowel disease | ileitis | mucosal | mesenchymal I nflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from inappropriate and sustained activation of the mucosal immune system against the bacterial microflora of the gut (1). IBD is represented by two major forms: ulcerative colitis (UC), which is manifested in the colon, and Crohn disease (CD), which is manifested primarily in the ileum but also in the colon (2). Genome-wide association studies in patients with CD indicate a putative role for genes of the innate and adaptive immunity system and an emerging role for genes implicated in autophagy (3). Animal models of disease suggest that adaptive immune responses are required for disease manifestation and that the gut microflora appear to drive inflammation (4). However, the exact mechanisms underlying IBD pathogenesis and especially the early pathogenic events remain largely obscure.TNF is critically implicated in IBD pathophysiology, highlighted by the successful use of anti-TNF therapies for the treatment of patients who have CD (5). TNF is shown to exert pathogenic activities in several animal models of IBD (6), whereas protective roles have been described also (7,8). The crucial pathogenic role of TNF in CD has been verified experimentally in mice that bear the genetic deletion of the TNF AUrich regulatory elements (ARE) that leads to defective posttranscriptional regulation of tnf expression and chronic TNF overproduction (9). Tnf ΔARE/+ mice chronically overprodu...
We have generated a free access, nonprofit online analytical database of somatic EGFR mutations in NSCLC. Cumulative information will be made available through a routine update of both database tables and associated graphical representations. Direct updates and submissions through the online site (www.somaticmutations-EGFR.org) are encouraged, as are comments and suggestions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.