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Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1? and Interleukin-18 from Human Monocytes.

ABSTRACT: Inflammasomes cleave and activate interleukin- (IL-) 1? and IL-18 which have both shared and unique biological functions. IL-1? is an important mediator of the acute phase response to infections and tissue damage, whereas IL-18 takes part in activation and tailoring of the adaptive immune response. While IL-1? has served as the prototypic indicator of inflammasome activation, few studies have compared the potential differences in IL-1? and IL-18 production during inflammasome activation. Since these cytokines partake in different immune pathways, the involvement of inflammasome activity in different conditions needs to be described beyond IL-1? production alone. To address a potential heterogeneity in inflammasome functionality, ATP, chitosan, or silica oxide (SiO2) were used to induce NLRP3 inflammasome activation in THP-1 cells and the subsequent outcomes were quantified. Despite using doses of the inflammasome inducers yielding similar release of IL-1?, SiO2-stimulated cells showed a lower concentration of released IL-18 compared to ATP and chitosan. Hence, the cells stimulated with SiO2 responded with a distinctly different IL-18 : IL-1? ratio. The difference in the IL-18 : IL-1? ratio for SiO2 was constant over different doses. While all downstream responses were strictly dependent on a functional NLRP3 inflammasome, the differences did not depend on the level of gene expression, caspase-1 activity, or pyroptosis. We suggest that the NLRP3 inflammasome response should be considered a dynamic process, which can be described by taking the ratio between IL-1? and IL-18 into account and moving away from an on/off perspective of inflammasome activation.

SUBMITTER: Midtbo K

PROVIDER: S-EPMC7599400 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1β and Interleukin-18 from Human Monocytes.

Midtbö Kristine K Eklund Daniel D Särndahl Eva E Persson Alexander A

Mediators of inflammation 20201022

Inflammasomes cleave and activate interleukin- (IL-) 1β and IL-18 which have both shared and unique biological functions. IL-1β is an important mediator of the acute phase response to infections and tissue damage, whereas IL-18 takes part in activation and tailoring of the adaptive immune response. While IL-1β has served as the prototypic indicator of inflammasome activation, few studies have compared the potential differences in IL-1β and IL-18 production during infl ...[more]

PMID: 33144845

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Project description:BACKGROUND & AIMS:Production of interferon (IFN)-? by natural killer (NK) cells is attenuated during chronic infection with hepatitis C virus (HCV). We investigated whether this is due to intrinsic or extrinsic mechanisms of NK cells. METHODS:Peripheral blood mononuclear cells (PBMCs) were collected from patients with chronic HCV infection or uninfected blood donors (controls); NK cells and monocytes were isolated or eliminated. We cultured hepatoma cells that express luciferase-tagged subgenomic HCV replicons (Huh7/HCV replicon cells) or their HCV-negative counterparts (Huh7) with NK cells in the presence or absence of other populations of PBMCs. Antiviral activity, cytotoxicity, and cytokine production were assessed. RESULTS:NK cells produced greater amounts of IFN-? when PBMC were cocultured with Huh7/HCV replicon cells than with Huh7 cells; NK cells and PBMCs from controls suppressed HCV replication to a greater extent than those from patients with chronic HCV infection. This antiviral effect was predominantly mediated by tumor necrosis factor (TNF)-? and IFN-?. The antiviral activity of NK cells and their production of IFN-? were reduced when they were used in coculture alone (rather than with PBMC), or after depletion of CD14(+) monocytes, after knockdown of the inflammasome in monocytes, or after neutralization of interleukin-18, which is regulated by the inflammasome. These findings indicate a role for monocytes in NK cell activation. Compared with control monocytes, monocytes from patients with chronic HCV infection had reduced TNF-?-mediated (direct) and reduced NK cell-mediated (indirect) antiviral effects. Control monocytes increased the antiviral effects of NK cells from patients with chronic HCV infection and their production of IFN-?. CONCLUSIONS:Monocytes sense cells that contain replicating HCV and respond by producing interleukin-18 via the inflammasome and by activating NK cells. Patients with chronic HCV infection have reduced monocyte function, attenuating NK cell IFN-?-mediated responses.

Dataset Information

Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1? and Interleukin-18 from Human Monocytes.

Publications

Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1<i>β</i> and Interleukin-18 from Human Monocytes.

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