Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.
Dimitris L. Kontoyiannis,George Boulougouris,Menelaos Manoloukos,Maria Armaka,Maria Apostolaki,Theresa T. Pizarro,Alexey Kotlyarov,Irmgard Förster,Richard A. Flavell,Matthias Gaestel,Philip N. Tsichlis,Fabio Cominelli,George Kollias +12 more
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It is shown 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 and the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease is established.Abstract:
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 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.read more
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Mitogen-activated protein kinases in innate immunity
J. Simon C. Arthur,Steven C. Ley +1 more
TL;DR: This Review discusses the current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage and how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence.
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Mammalian MAPK Signal Transduction Pathways Activated by Stress and Inflammation: A 10-Year Update
John M. Kyriakis,Joseph Avruch +1 more
TL;DR: The molecular components of the mammalian stress-regulated MAPK pathways and their regulation as described thus far are summarized and some of the in vivo functions of these pathways are reviewed.
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Functions of NF-κB1 and NF-κB2 in immune cell biology
Sören Beinke,Steven C. Ley +1 more
TL;DR: In this article, the authors focus on the latest advances in research on the function of NF-κB1/Rel transcription factor in immune cells and present a review of the most recent advances in this area.
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Mouse models of inflammatory bowel disease.
Stefan Wirtz,Markus F. Neurath +1 more
TL;DR: A brief overview of selected mouse models of IBD are provided and their contribution to the current understanding of disease mechanisms that contribute to IBD is discussed.
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Experimental Models of Inflammatory Bowel Disease Reveal Innate, Adaptive, and Regulatory Mechanisms of Host Dialogue With the Microbiota
Charles O. Elson,Yingzi Cong,Vance J. McCracken,Reed A. Dimmitt,Robin G. Lorenz,Casey T. Weaver +5 more
TL;DR: The thesis is advanced that ‘multiple hits’ or defects in these interacting components is required for IBD to occur in both mouse and human.
References
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The TNF and TNF receptor superfamilies: integrating mammalian biology.
TL;DR: The authors regret the inability to cite all of the primary literature contributing to this review due to length considerations, but wish to thank F. Chan, T. Migone, and J. Wang for insightful comments on the manuscript.
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Conditional gene targeting in macrophages and granulocytes using LysMcre mice.
TL;DR: The generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus is reported, allowing for both specific and highly efficient Cre–mediated deletion of loxP–flanked target genes in myELoid cells.
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A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene
TL;DR: The importance of the membrane form of the μ chain in B-cell development is assessed by generating mice lacking this chain by disrupting one of the membranes exons of the gene encoding the μ-chain constant region by gene targeting in mouse embryonic stem cells.
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Multiple defects of immune cell function in mice with disrupted interferon-gamma genes
TL;DR: IFN-gamma is essential for the function of several cell types of the murine immune system and has impaired production of macrophage antimicrobial products and reduced expression of Macrophage major histocompatibility complex class II antigens.
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MAP Kinases in the Immune Response
TL;DR: Recent progress in understanding the function and regulation of MAP kinase pathways in these phases of immune responses in mammalian species is summarized.