PLoS Pathogens | |
Activity of Uncleaved Caspase-8 Controls Anti-bacterial Immune Defense and TLR-Induced Cytokine Production Independent of Cell Death | |
Andrew Oberst1  Jennifer T. Grier2  Meghan A. Wynosky-Dolfi2  Alexandra DeLaney2  Igor E. Brodsky2  Lance W. Peterson3  Jorge Henao-Mejia3  Naomi H. Philip3  Anthony Rongvaux3  Erin E. Zwack3  Melanie Santos-Marrero3  Baofeng Hu3  Yan Sun3  Tayla M. Olsen3  Scott D. Pope3  Carolina B. López4  Daniel P. Beiting5  | |
[1] Fred Hutchinson Cancer Research Center, Clinical Research Division and Program in Immunology, Seattle, Washington, United States of America;University of Pennsylvania Perelman School of Medicine, Institute for Immunology, Philadelphia, Pennsylvania, United States of America;University of Pennsylvania School of Veterinary Medicine, Department of Pathobiology, Philadelphia, Pennsylvania, United States of America;University of Washington, Department of Immunology, Seattle, Washington, United States of America;Yale University School of Medicine, Department of Immunobiology, New Haven, Connecticut, United States of America | |
关键词: Gene expression; Cytokines; Inflammation; Apoptosis; Yersinia; Macrophages; Gene regulation; Necrosis; | |
DOI : 10.1371/journal.ppat.1005910 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
Caspases regulate cell death programs in response to environmental stresses, including infection and inflammation, and are therefore critical for the proper operation of the mammalian immune system. Caspase-8 is necessary for optimal production of inflammatory cytokines and host defense against infection by multiple pathogens including Yersinia, but whether this is due to death of infected cells or an intrinsic role of caspase-8 in TLR-induced gene expression is unknown. Caspase-8 activation at death signaling complexes results in its autoprocessing and subsequent cleavage and activation of its downstream apoptotic targets. Whether caspase-8 activity is also important for inflammatory gene expression during bacterial infection has not been investigated. Here, we report that caspase-8 plays an essential cell-intrinsic role in innate inflammatory cytokine production in vivo during Yersinia infection. Unexpectedly, we found that caspase-8 enzymatic activity regulates gene expression in response to bacterial infection as well as TLR signaling independently of apoptosis. Using newly-generated mice in which caspase-8 autoprocessing is ablated (Casp8DA/DA), we now demonstrate that caspase-8 enzymatic activity, but not autoprocessing, mediates induction of inflammatory cytokines by bacterial infection and a wide variety of TLR stimuli. Because unprocessed caspase-8 functions in an enzymatic complex with its homolog cFLIP, our findings implicate the caspase-8/cFLIP heterodimer in control of inflammatory cytokines during microbial infection, and provide new insight into regulation of antibacterial immune defense.
【 授权许可】
CC BY
【 预 览 】
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