Cutting edge: ASC mediates the induction of multiple cytokines by Porphyromonas gingivalis via caspase-1-dependent and -independent pathways.
Debra J. Taxman,Jinghua Zhang,Catherine M. E. Champagne,Daniel T. Bergstralh,Heather A. Iocca,John D. Lich,Jenny P.-Y. Ting +6 more
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TLDR
A role for ASC is suggested in cytokine induction by Pg involving both caspase-1-dependent and -independent mechanisms, and broad applicability of these findings are indicated.Abstract:
Porphyromonas gingivalis (Pg) is a major etiologic agent for chronic periodontitis. Tissue destruction by Pg results partly from induction of host inflammatory responses through TLR2 signaling. This work examines the role of apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), an adaptor molecule important for TLR-mediated caspase-1 activation. Results demonstrate that ASC levels are stable upon infection of human THP1 monocytic cells with Pg but decrease after cytokine induction. Using short hairpin RNA, we demonstrate an essential role for ASC in induction of IL-1β by TLR2, 4, and 5 agonists, live Escherichia coli, and Pg. Induction of IL-6, IL-8, IL-10, and TNF also requires ASC, but this induction is not inhibited by IL-1 receptor antagonist or caspase-1 inhibitor. Similar results in U937 indicate broad applicability of these findings. Pg-infected ASC knockdown THP1 cells exhibit reduced transcript levels and NF-κB activation. These results suggest a role for ASC in cytokine induction by Pg involving both caspase-1-dependent and -independent mechanisms.read more
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Journal ArticleDOI
The NLRP3 Inflammasome Mediates in vivo Innate Immunity to Influenza A Virus through Recognition of Viral RNA
Irving C. Allen,Margaret A. Scull,Chris B. Moore,Eda K. Holl,Erin McElvania-TeKippe,Debra J. Taxman,Elizabeth H. Guthrie,Raymond J. Pickles,Jenny P.-Y. Ting +8 more
TL;DR: Mechanistically, NLRP3 inflammasome activation by the influenza virus was dependent on lysosomal maturation and reactive oxygen species (ROS), and inhibition of ROS induction eliminated IL-1beta production in animals during influenza infection.
Journal ArticleDOI
The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
Irving C. Allen,Erin McElvania TeKippe,Rita Marie T Woodford,Joshua M. Uronis,Eda K. Holl,Arlin B. Rogers,Hans H Herfarth,Christian Jobin,Jenny P.-Y. Ting +8 more
TL;DR: Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis, suggesting that the inflammasome functions as an attenuator of colitis and CAC.
Journal ArticleDOI
Cutting Edge: Inflammasome activation by Alum and Alum’s adjuvant effect are mediated by NLRP3
TL;DR: It is shown that alum-induced secretion of IL-1β, IL-18, and IL-33 is mediated by the NLR (nucleotide-binding domain leucine-rich repeat-containing) protein NLRP3 and its adaptor ASC, but not by NLRC4, suggesting that activation of theNLRP3-inflammasome may be a common mechanism of action of particulate adjuvants.
Journal ArticleDOI
Staphylococcus aureus α-Hemolysin Activates the NLRP3-Inflammasome in Human and Mouse Monocytic Cells
Robin R. Craven,Xi Gao,Irving C. Allen,Denis Gris,Juliane Bubeck Wardenburg,Erin McElvania-TeKippe,Jenny P.-Y. Ting,Joseph A. Duncan +7 more
TL;DR: It is demonstrated that α-hemolysin activates the Nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 protein -inflammasome, a host inflammatory signaling complex involved in responses to pathogens and endogenous danger signals, and works in conjunction with signaling by other CA-MRSA-derived Pathogen Associated Molecular Patterns (PAMPs) to induce secretion of pro-inflammatory cytokines IL-1β and IL-18.
Book ChapterDOI
Short hairpin RNA (shRNA): design, delivery, and assessment of gene knockdown.
TL;DR: These studies demonstrate the practicality of including two shRNAs with different efficacies of knockdown to provide an additional level of control and to verify dose dependency of functional effects, and suggest suggestions for designing shRNA targets and controls.
References
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The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.
TL;DR: In this article, the inflammasome is identified as a caspase-activating complex that comprises caspases-1, casp-5, Pycard/Asc, and NALP1, a Pyrin domain-containing protein sharing structural homology with NODs.
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TL;DR: Purification and cloning of the complementary DNA indicates that IL-lβ-converting enzyme is composed of two nonidentical subunits that are derived from a single proenzyme, possibly by autoproteolysis.
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Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf.
Sanjeev Mariathasan,Kim Newton,Denise M. Monack,Domagoj Vucic,Dorothy French,Wyne P. Lee,Meron Roose-Girma,Sharon Erickson,Vishva M. Dixit +8 more
TL;DR: Interestingly, cell death triggered by stimuli that engage caspase-1 was ablated in macrophages lacking either ASC or Ipaf, suggesting a coupling between the inflammatory and cell death pathways.
Journal ArticleDOI
Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor
Hannum Charles H,Carol J. Wilcox,William P. Arend,Joslin Fenneke G,David Dripps,Patricia L. Heimdal,Lyman G Armes,Andreas Sommer,Stephen P. Eisenberg,Robert C. Thompson +9 more
TL;DR: Three interleukin-1 inhibitors have been purified to homogeneity from medium conditioned by human monocytes and partial sequence analysis and digestion with N-glycanase indicate that these are glycosylation forms of a single protein.
Journal ArticleDOI
Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages.
Matthew Hirschfeld,Janis J. Weis,Vladimir Y. Toshchakov,Cindy A. Salkowski,M. Joshua Cody,Dawn C. Ward,Nilofer Qureshi,Suzanne M. Michalek,Stefanie N. Vogel +8 more
TL;DR: These studies demonstrate that in contrast to protein-free enterobacterial LPS, a similarly purified preparation of P. gingivalis LPS exhibited potent Toll-like receptor 2 (TLR2), rather than TLR4, agonist activity to elicit gene expression and cytokine secretion in murine macrophages and transfectants.