Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression
Jane C. Goodall,Changxin Wu,Yongsheng Zhang,Louise McNeill,Lou Ellis,Vladimir Saudek,J. S. Hill Gaston +6 more
TLDR
Investigation of proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress found the IL-23 gene was found to be a target of the ER stress-induced transcription factor C/EBP homologous protein (CHOP), which exhibited enhanced binding in the context of both ER stress and TLR stimulation.Abstract:
The endoplasmic reticulum (ER) stress response detects malfunctions in cellular physiology, and microbial pattern recognition receptors recognize external threats posed by infectious agents. This study has investigated whether proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress. Activation of ER stress, in combination with Toll-like receptor (TLR) agonists, markedly enhanced expression of mRNA of the unique p19 subunit of IL-23, and also significantly augmented secretion of IL-23 protein. These effects were not seen for IL-12 secretion. The IL-23 gene was found to be a target of the ER stress-induced transcription factor C/EBP homologous protein (CHOP), which exhibited enhanced binding in the context of both ER stress and TLR stimulation. Knockdown of CHOP in U937 cells significantly reduced the synergistic effects of TLR and ER stress on IL-23p19 expression, but did not affect expression of other LPS-responsive genes. The integration of ER stress signals and the requirement for CHOP in the induction of IL-23 responses was also investigated in a physiological setting: infection of myeloid cells with Chlamydia trachomatis resulted in the expression of CHOP mRNA and induced the binding of CHOP to the IL-23 promoter. Furthermore, knockdown of CHOP significantly reduced the expression of IL-23 in response to this intracellular bacterium. Therefore, the effects of pathogens and other environmental factors on ER stress can profoundly affect the nature of innate and adaptive immune responses.read more
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Genetics and pathogenesis of inflammatory bowel disease
TL;DR: Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease, and the role of genetic predispositions and how they affect interactions with microbial and environmental factors is emphasized.
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TL;DR: A greater fundamental understanding of the mechanisms that preserve protein folding homeostasis and redox status will provide new information toward the development of novel therapeutics for many human diseases.
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IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells
Jonathan P Sherlock,Barbara Joyce-Shaikh,Scott P. Turner,Cheng-Chi Chao,Manjiri Sathe,Jeff Grein,Daniel M. Gorman,Edward P. Bowman,Terrill K. McClanahan,Jennifer H. Yearley,Gérard Eberl,Christopher D. Buckley,Robert A. Kastelein,Robert H. Pierce,Drake LaFace,Daniel J. Cua +15 more
TL;DR: It is shown here that IL-23 is essential in enthesitis and acts on previously unidentified IL- 23 receptor (IL-23R)+, RAR-related orphan receptor γt (ROR-γt)+CD3+CD4−CD8−, stem cell antigen 1 (Sca1)+ entheseal resident T cells, which allow entheses to respond to IL-21 in vitro—in the absence of further cellular recruitment—and to elaborate inflammatory mediators
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The impact of the endoplasmic reticulum protein-folding environment on cancer development.
Miao Wang,Randal J. Kaufman +1 more
TL;DR: The impact of ER stress and UPR activation on every aspect of cancer is summarized and outstanding questions for which answers will pave the way for therapeutics are discussed.
References
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XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response
TL;DR: It is suggested that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP- 1.
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The UCSC Genome Browser database: update 2011
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TL;DR: New data highlights include seven new genome assemblies, a Neandertal genome data portal, phenotype and disease association data, a human RNA editing track, and a zebrafish Conservation track.
Journal ArticleDOI
CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
Stefan J. Marciniak,Chi Yun,Seiichi Oyadomari,Isabel Novoa,Yuhong Zhang,Rivka Jungreis,Kazuhiro Nagata,Heather P. Harding,David Ron +8 more
TL;DR: This work finds that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells, and protects cells from ER stress by decreasing client protein load and changing redox conditions within the organelle.
Journal ArticleDOI
ER stress and the unfolded protein response.
TL;DR: A model in which the activity of UPR signaling pathways reflects the biosynthetic activity of the ER is proposed, which shows that this information is integrated into control of cellular events, which were previously not considered to be under control of ER signaling pathways.
Journal ArticleDOI
Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation
Craig A. Murphy,Claire L. Langrish,Yi Yi Chen,Wendy M. Blumenschein,Terrill K. McClanahan,Robert A. Kastelein,Jonathon D. Sedgwick,Daniel J. Cua +7 more
TL;DR: The data presented here indicate that IL-23 is an essential promoter of end-stage joint autoimmune inflammation, whereas IL-12 paradoxically mediates protection from autoimmune inflammation.
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