Cutting Edge: ASC Mediates the Induction of Multiple Cytokines by <i>Porphyromonas gingivalis</i> via Caspase-1-Dependent and -Independent Pathways

Taxman, Debra J.; Zhang, Jinghua; Champagne, Catherine M.; Bergstralh, Daniel T.; Iocca, Heather A.; Lich, John D.; Ting, Jenny P.Y.

doi:10.4049/jimmunol.177.7.4252

Cited by 70 publications

(117 citation statements)

References 24 publications

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“…Interestingly, the expression of the adaptor molecule ASC, that mediates NLR binding to Caspase-1, is down-regulated by A. actinomycetemcomitans infection. These results are in agreement with the up-regulation of NLRP3 [26] and down-regulation of ASC [26,54] in myelomonocytic Monomac-6 or monocytic THP1 cells, by the major periodontal pathogen Porphyromonas gingivalis. Similar findings were are also demonstrated in another experimental system, in which Listeria monocytogenes is shown to up-regulate NLRP3, but down-regulate NLRP6 and ASC expression in human peripheral blood mononuclear cells [55].…”

Section: Discussionsupporting

confidence: 89%

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Belibasakis

Johansson

2012

Cytokine

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Periodontitis is an inflammatory condition that destroys the tooth-supporting tissues, as a result of local bacterial infection. Aggregatibacter actinomycetemcomitans is a Gram-negative facultative anaerobic species, highly associated with aggressive periodontitis. Periodontal inflammation is dominated by cytokines of the Interleukin (IL)-1 family. Prior to their secretion by mononuclear cells, IL-1 cytokines are processed by intracellular protein complexes, known as "inflammasomes", which can sense the bacterial challenge. The aim of this study was to investigate which inflammasomes are regulated in mononuclear cells in response to A. actinomycetemcomitans. The D7SS strain and its derivative leukotoxin and cytolethal distending toxin knock-out mutant strains were used to infect human mononuclear cells at a 1:10 cell: bacteria ratio, for 3 h. The expression of various inflammasome components in the cells was investigated by TaqMan quantitative real-time polymerase chain reaction (qPCR). The expressions of NOD-like receptor protein (NLRP)1, NLRP2 and Absent In Melanoma (AIM)2 inflammasome sensors, as well as their effector Caspase-1 were not affected. However, NLRP3 was up-regulated, while NLRP6 was down-regulated. This effect was not dependent on the leukotoxin or the cytolethal distending toxin, as demonstrated by the use of specific gene knock-out mutant strains. IL-1 and IL-18 expressions were also up-regulated by the bacterial challenge. In conclusion, A. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation. actinomycetemcomitans enhances NLRP3 and reduces NLRP6 inflammasome expression, irrespective of its major virulence factors, confirming the high pathogenic profile of this species, and providing further insights to the mechanisms of periodontal inflammation.

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Section: Discussionsupporting

confidence: 89%

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Belibasakis

Johansson

2012

Cytokine

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“…ASC is reported to be required for the induction not only of IL-1β, IL-18, but also of IL-6, IL-8, IL-10, and TNF through both caspase-1-dependent and -independent mechanisms [25].…”

Section: Discussionmentioning

confidence: 99%

Exercise Effects on Methylation ofASCGene

et al. 2010

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Chronic moderate exercise has been reported to reduce pro-inflammatory cytokines. To analyze the molecular mechanisms by which training exerts these effects, the epigenetic influences of age and exercise on the ASC gene, which is responsible for IL-1β and IL-18 secretion, were investigated by ASC gene methylation. Further, the relationship between carcinogenesis and exercise, methylation of the p15 tumor suppressive gene was analyzed as well. High-intensity interval walking exercise, consisting of 3-minute low-intensity walking at 40% of peak aerobic capacity followed by a 3-minute high-intensity walking period above 70% of peak aerobic capacity, was continued for 6 months. Peripheral blood DNA extracts from young control (n=34), older control (n=153), and older exercise (n=230) groups were then analyzed by pyrosequencing for DNA methylation. Methylation of ASC decreased significantly with age (young control vs. older control, p<.01), which is indicative of an age-dependent increase in ASC expression. Compared to the older control group, the degree of ASC methylation was higher in the older exercise group (older control vs. older exercise:, p<.01) and presumably lower ASC expression. Neither exercise nor age affected the methylation of the p15. In summary, chronic moderate exercise appears to attenuate the age-dependent decrease in ASC methylation, implying suppression of excess pro-inflammatory cytokines through reduction of ASC expression.

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“…ShASC#1, shASC#2, and shASC#1mut THP1 cell lines were generated using retroviral vectors and have been characterized previously (18,23). DUSP10-expressing THP1 cells were generated using the full-length open reading frame cloned into lentiviral vector pLex-JRed (catalogue #OHS4493-98905681; Open Biosystems).…”

Section: Generation Of Cell Lines Isolation Of Mouse Macrophagesmentioning

confidence: 99%

“…Although periodontal disease is localized to the tissues surrounding the tooth, Pg infection predisposes people to more serious systemic conditions such as cardiovascular disease and delivery of preterm infants (29,31,32). Recently, we showed that, during Pg infection, ASC exhibits inflammasome-independent functions, including TNF-␣ and NF-B activation (23). We therefore elected to use this pathogen to reveal new ASC functions that might be separable from that of the inflammasome.…”

mentioning

confidence: 99%

“…A requirement for Asc, but not Nlrp3 or Caspase-1, was also recently demonstrated for antigen-specific humoral immunity after vaccination with MF59-adjuvented influenza (22). ASC has been proposed to regulate cytokine transcription through activation of NF-B (23,24). AP1, STAT3, ISGF3, and NF-AT have also been identified as transcriptional ASC targets in a reconstituted cell system with exogenously expressed ASC and a chimeric CARD12/NOD2 protein (25).…”

mentioning

confidence: 99%

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The NLR Adaptor ASC/PYCARD Regulates DUSP10, Mitogen-activated Protein Kinase (MAPK), and Chemokine Induction Independent of the Inflammasome

Taxman¹,

Holley-Guthrie²,

Huang³

et al. 2011

Journal of Biological Chemistry

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ASC/PYCARD is a common adaptor for a diverse set of inflammasomes that activate caspase-1, most prominently the NLR-based inflammasome. Mounting evidence indicates that ASC and these NLRs also elicit non-overlapping functions, but the molecular basis for this difference is unclear. To address this, we performed microarray and network analysis of ASC shRNA knockdown cells. In pathogen-infected cells, an ASCdependent interactome is centered on the mitogen-activated protein kinase (MAPK) ERK and on multiple chemokines. ASC did not affect the expression of MAPK but affected its phosphorylation by pathogens and Toll-like receptor agonists via suppression of the dual-specificity phosphatase, DUSP10/MKP5. Chemokine induction, DUSP function, and MAPK phosphorylation were independent of caspase-1 and IL-1␤. MAPK activation by pathogen was abrogated in Asc ؊/؊ but not Nlrp3 ؊/؊ , Nlrc4 ؊/؊ , or Casp1 ؊/؊ macrophages. These results demonstrate a function for ASC that is distinct from the inflammasome in modulating MAPK activity and chemokine expression and further identify DUSP10 as a novel ASC target.

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Cutting Edge: ASC Mediates the Induction of Multiple Cytokines by Porphyromonas gingivalis via Caspase-1-Dependent and -Independent Pathways

Cited by 70 publications

References 24 publications

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes

Exercise Effects on Methylation ofASCGene

The NLR Adaptor ASC/PYCARD Regulates DUSP10, Mitogen-activated Protein Kinase (MAPK), and Chemokine Induction Independent of the Inflammasome

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