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Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.
Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis
The Artificial Sweetener Splenda Promotes Gut Proteobacteria, Dysbiosis, and Myeloperoxidase Reactivity in Crohn’s Disease–Like Ileitis
We thank John D. Ward and Lindsey N. Kaydo for their technical support and Dr. Wei Xin for the histological scoring of ileitis severity. ARP is an Assistant Professor of Medicine at CWRU School of Medicine. Metagenomic sequencing was conducted in the laboratory of Dr. Skip Virgin at Washington University, School of Medicine, St. Louis, MO. Raw sequencing data files will be available upon request.Peer reviewedPostprin
Target highlights in CASP9: Experimental target structures for the critical assessment of techniques for protein structure prediction
15 pags, 9 figsOne goal of the CASP community wide experiment on the critical assessment of techniques for protein structure prediction is to identify the current state of the art in protein structure prediction and modeling. A fundamental principle of CASP is blind prediction on a set of relevant protein targets, that is, the participating computational methods are tested on a common set of experimental target proteins, for which the experimental structures are not known at the time of modeling. Therefore, the CASP experiment would not have been possible without broad support of the experimental protein structural biology community. In this article, several experimental groups discuss the structures of the proteins which they provided as prediction targets for CASP9, highlighting structural and functional peculiarities of these structures: the long tail fiber protein gp37 from bacteriophage T4, the cyclic GMP-dependent protein kinase Iβ dimerization/docking domain, the ectodomain of the JTB (jumping translocation breakpoint) transmembrane receptor, Autotaxin in complex with an inhibitor, the DNA-binding J-binding protein 1 domain essential for biosynthesis and maintenance of DNA base-J (β-D-glucosyl-hydroxymethyluracil) in Trypanosoma and Leishmania, an so far uncharacterized 73 residue domain from Ruminococcus gnavus with a fold typical for PDZ-like domains, a domain from the phycobilisome core-membrane linker phycobiliprotein ApcE from Synechocystis, the heat shock protein 90 activators PFC0360w and PFC0270w from Plasmodium falciparum, and 2-oxo-3-deoxygalactonate kinase from Klebsiella pneumoniae. © 2011 Wiley-Liss, Inc.Grant sponsor: Spanish Ministry of Education and Science; Grant number: BFU2008-01588; Grant sponsor: European Commission; Grant number: NMP4-CT-2006-033256; Grant sponsor: Spanish Ministry of Education and Science (José Castillejo fellowship); Grant sponsor: Xunta de Galicia (Angeles Alvariño fellowship); Grant sponsor: National Institutes of Health; Grant numbers: K22-CA124517 (D.E.C.); R01-GM090161 (C.K.) GM074942; GM094585; Grant sponsor: U. S. Department of Energy, Office of Biological and Environmental Research; Grant number: DE-AC02-06CH11357 (to A.J.); Grant sponsor: Foundation for Polish Science (to K.M.); Grant sponsor: NSF; Grant number: DBI 0829586
Challenges in IBD Research: Update on Progress and Prioritization of the CCFAʼs Research Agenda
Live or let die: Translational insights and clinical perspectives of gasdermin B‐dependent intestinal epithelial cell fate
The Treg/Th17 axis: A dynamic balance regulated by the gut microbiome
T-helper 17 (Th17) and T-regulatory (Treg) cells are frequently found at barrier surfaces, particularly within the intestinal mucosa, where they function to protect the host from pathogenic microorganisms and to restrain excessive effector T-cell responses, respectively. Despite their differing functional properties, Th17 cells and Tregs share similar developmental requirements. In fact, the fate of antigen-naïve T-cells to either Th17 or Treg lineages is finely regulated by key mediators, including TGFβ, IL-6 and all-trans retinoic acid (RA). Importantly, the intestinal microbiome also provides immunostimulatory signals, which can activate innate, and downstream adaptive, immune responses. Specific components of the gut microbiome have been implicated in the production of proinflammatory cytokines by innate immune cells, such as IL-6, IL-23, IL-1β, and the subsequent generation and expansion of Th17 cells. Similarly, commensal bacteria and their metabolites can also promote the generation of intestinal Tregs that can actively induce mucosal tolerance. As such, dysbiosis of the gut microbiome may not solely represent a consequence of gut inflammation, but rather shape the Treg/Th17 commitment and influence susceptibility to inflammatory bowel disease (IBD). In this review, we discuss Treg and Th17 cell plasticity, its dynamic regulation by the microbiome, and highlight its impact on intestinal homeostasis and disease
Immunological Regulation of Intestinal Fibrosis in Inflammatory Bowel Disease
Intestinal fibrosis is a late-stage phenotype of inflammatory bowel
disease (IBD), which underlies most of the long-term complications and
surgical interventions in patients, particularly those with Crohn's
disease. Despite these issues, antifibrotic therapies are still scarce,
mainly due to the current lack of understanding concerning the
pathogenetic mechanisms that mediate fibrogenesis in patients with
chronic intestinal inflammation. In the current review, we summarize
recent evidence regarding the cellular and molecular factors of innate
and adaptive immunity that are considered critical for the initiation
and amplification of extracellular matrix deposition and stricture
formation. We focus on the role of cytokines by dissecting the pro- vs
antifibrotic components of the immune response, while taking into
consideration their temporal association to the progressive stages of
the natural history of IBD. We critically present evidence from animal
models of intestinal fibrosis and analyze inflammation-fibrosis
interactions that occur under such experimental scenarios. In addition,
we comment on recent findings from large-scale, single-cell profiling of
fibrosis-relevant populations in IBD patients. Based on such evidence,
we propose future potential targets for antifibrotic therapies to treat
patients with IBD.
Lay Summary In this review, authors describe the cellular and molecular
immunological mechanism(s) of intestinal fibrosis in IBD, with a
particular focus on animal models of intestinal fibrosis
754 Gut Microflora Promotes Expression/Function of IL-17F+ Tregs and Gender-Associated Disease Severity in Experimental Ileitis
New insights into the dichotomous role of innate cytokines in gut homeostasis and inflammation
In addition to their well-known role in acute injury and chronic
inflammation, “innate” cytokines play an important role in health
and the maintenance of normal immune homeostasis. This group includes
the prototypic cytokines IL-1 and TNF alpha, as well as several other
members belonging to the IL-1 and TNF family, such as IL-18, IL-33,
IL-36-38, and TL1A. The dichotomous role of these cytokines has been
best characterized in the intestine where innate cytokines may play both
a protective and a pro-inflammatory role, depending upon the
immmunological status of the host or the type and phase of the
inflammatory process. This new information has produced novel
pathogenetic hypotheses that have important translational implications
both in regard to the prevention and treatment of chronic intestinal
inflammation, including Crohn’s disease and ulcerative colitis, the two
major forms of inflammatory bowel disease. This review will discuss and
summarize current data regarding the role of IL-1, TNF alpha, and their
family members in regulating gut mucosal homeostasis and chronic
intestinal inflammation. (C) 2012 Published by Elsevier Ltd
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