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Myeloid-derived NF-?B negative regulation of PU.1 and c/EBP-?-driven pro-inflammatory cytokine production restrains LPS-induced shock.

ABSTRACT: Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (M?) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1?, IL-6 and TNF-? production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-?B signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65?mye) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1? and IL-6. Mechanistic analyses revealed that LPS-induced pro-inflammatory cytokine production was ameliorated in p65-deficient bone marrow-derived M?s; however, p65-deficient 'activated' peritoneal M?s exhibited elevated IL-1? and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1? mRNA and protein in activated inflammatory M?s. The increased IL-1? was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-? to Il1b and Il6 promoters in activated inflammatory M?s. Our data provide insight into a role for NF-?B in the negative regulation of pro-inflammatory cytokines in myeloid cells.

SUBMITTER: Vanoni S

PROVIDER: S-EPMC5563821 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-β-driven pro-inflammatory cytokine production restrains LPS-induced shock.

Vanoni Simone S Tsai Yi-Ting YT Waddell Amanda A Waggoner Lisa L Klarquist Jared J Divanovic Senad S Hoebe Kasper K Steinbrecher Kris A KA Hogan Simon P SP

Innate immunity 20161208 2

Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (MΦ) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-κB signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we ...[more]

PMID: 27932520

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Project description:BackgroundAbility to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Heat Shock (HS) affects the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor, a critical regulator of proliferation and inflammation, however, our quantitative understanding of how cells sense and adapt to temperature changes is limited.MethodsWe used live-cell time-lapse microscopy and mathematical modelling to understand the signalling of the NF-κB system in the human MCF7 breast adenocarcinoma cells in response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines, following exposure to a 37-43 °C range of physiological and clinical temperatures.ResultsWe show that exposure to 43 °C 1 h HS inhibits the immediate NF-κB signalling response to TNFα and IL1β stimulation although uptake of cytokines is not impaired. Within 4 h after HS treatment IL1β-induced NF-κB responses return to normal levels, but the recovery of the TNFα-induced responses is still affected. Using siRNA knock-down of Heat Shock Factor 1 (HSF1) we show that this stimulus-specificity is conferred via the Inhibitory κB kinase (IKK) signalosome where HSF1-dependent feedback regulates TNFα, but not IL1β-mediated IKK recovery post HS. Furthermore, we demonstrate that through the temperature-dependent denaturation and recovery of IKK, TNFα and IL1β-mediated signalling exhibit different temperature sensitivity and adaptation to repeated HS when exposed to a 37-43 °C temperature range. Specifically, IL1β-mediated NF-κB responses are more robust to temperature changes in comparison to those induced by TNFα treatment.ConclusionsWe demonstrate that the kinetics of the NF-κB system following temperature stress is cytokine specific and exhibit differential adaptation to temperature changes. We propose that this differential temperature sensitivity is mediated via the IKK signalosome, which acts as a bona fide temperature sensor trough the HSR cross-talk. This novel quantitative understanding of NF-κB and HSR interactions is fundamentally important for the potential optimization of therapeutic hyperthermia protocols. Video Abstract.

Dataset Information

Myeloid-derived NF-?B negative regulation of PU.1 and c/EBP-?-driven pro-inflammatory cytokine production restrains LPS-induced shock.

Publications

Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-β-driven pro-inflammatory cytokine production restrains LPS-induced shock.

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