Primer: inflammasomes and interleukin 1β in inflammatory disorders

Church, Leigh D; Cook, Graham P.; McDermott, Michael F.

doi:10.1038/ncprheum0681

Cited by 285 publications

(208 citation statements)

References 70 publications

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“…Reflecting the differential responsiveness at the transcriptome level, protein levels for the evaluated cytokines varied among these myeloid populations, as shown for IL-l␤, IL-6, and also TNF-␣ (Figure 3 and Figure 7, A and B). However, in keeping with the requirement for posttranscriptional inflammasome-mediated processing of the IL-l␤ precursor protein, 29 macrophages and DCs secreted little active IL-l␤ protein ( Figure 7A), despite Ն100-fold increases in gene expression ( Figure 7A and Supplemental Table S2 available at http://ajp.amjpathol. org).…”

Section: Cytokines and Co-stimulatory Molecules Associated With Innatsupporting

confidence: 54%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigenpresenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation.

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Section: Cytokines and Co-stimulatory Molecules Associated With Innatsupporting

confidence: 54%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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“…A variety of single point mutations within the nucleotide binding domain or leucine-rich repeats alter the function of NLRP3 (56). Yet very little is known about the molecular requirements for NLRP3 inflammasome activation; thus, it is plausible that differences confer a Francisella-responsive state to NLRP3 that Nlrp3 lacks.…”

Section: Discussionmentioning

confidence: 99%

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

Atianand

Duffy

Shah

et al. 2011

Journal of Biological Chemistry

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Pathogen-triggered activation of the inflammasome complex leading to caspase-1 activation and IL-1␤ production involves similar sensor proteins between mouse and human. However, the specific sensors used may differ between infectious agents and host species. In mice, Francisella infection leads to seemingly exclusive activation of the Aim2 inflammasome with no apparent role for Nlrp3. Here we examine the IL-1␤ response of human cells to Francisella infection. Francisella strains exhibit differences in IL-1␤ production by influencing induction of IL-1␤ and ASC transcripts. Unexpectedly, our results demonstrate that Francisella activates the NLRP3 inflammasome in human cells. Innate immune responses to pathogens are initiated by recognition of pathogen-associated molecular patterns by both extracellular and intracellular sensors (1-3). Pathogen-associated molecular pattern recognition by members of the Toll-like receptor (TLR) 3 family result in the activation of the NF-B, MAPK, and/or interferon regulatory factor signaling pathways depending on the specific TLR engaged (1, 4 -8). Intracellular receptors of the MAVS/RIG-I family act similarly and are involved in recognition of viral nucleic acids (9, 10). Thus, production of inflammatory cytokines and chemokines such as TNF␣, IL-6, and MCP-1 in response to infection generally follows activation via these receptors. The inflammatory cytokines IL-1␤ and IL-18, however, require processing by caspase-1 to produce their active forms (11). Pathogen-associated molecular patterns and danger-associated molecular patterns activate various members of the nucleotide binding leucine-rich receptor (NLR) family in the cytoplasm, resulting in the assembly of an NLR containing, multiprotein complex (the inflammasome) that recruits and activates caspase-1 leading to IL-1␤ processing (12, 13). Although CARD domain-containing NLRs (e.g. Ipaf) can directly interact with caspase-1, most inflammasomes are assembled by Pyrin domain containing NLRs (NLRPs), which recruit caspase-1 indirectly through the adapter molecule ASC (14).Francisella tularensis is the causative agent of tularemia and a potential bioweapon (15). Pulmonary infection with even a single, virulent F. tularensis bacterium is potentially lethal if untreated (16,17). For humans, the type A strain, SchuS4 (F. tularensis sp. tularensis) results in the highest mortality, whereas neither the attenuated type B live vaccine strain LVS (F. tularensis sp. holarctica) or the U112 strain (Francisella tularensis sp. novicida) are virulent. In mice however, the SchuS4, LVS and U112 strains are lethal (18). Because of its importance in controlling bacterial infection and promoting adaptive immunity, the innate immune response to F. tularensis has been an area of recent interest. In mouse models of tularemia, the macrophage response to F. tularensis LVS is heavily reliant upon TLR2 as TLR2-deficient macrophages fail to produce TNF␣, IL-6, and other NF-B dependent proinflammatory cytokines (19,20). Mouse macrophages infected with U112 ...

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“…Interleukin 1 beta regulates inflammation signal pathway 28 and accelerates the expression level of MMP and TIMP. 29 It was reported that N-myc downstream regulated 1 regulates angiogenesis in hepatocellular carcinoma, 30 and B-cell leukemia/lymphoma 2 protein promotes apoptosis.…”

Section: Controlling Liver Fibrosis Through Preventionmentioning

confidence: 99%

MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice

et al. 2016

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Primer: inflammasomes and interleukin 1β in inflammatory disorders

Cited by 285 publications

References 70 publications

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Francisella tularensis Reveals a Disparity between Human and Mouse NLRP3 Inflammasome Activation

MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice

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