The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes

Galbraith, Norman; Manek, Stephen; Bishop, Campbell; Carter, Jane; Cahill, Meredith; Gardner, Sarah; Polk, Hiram C.; Galandiuk, Susan

doi:10.1016/j.imbio.2017.10.045

Cited by 8 publications

(13 citation statements)

References 38 publications

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“…Mean fluorescence intensity (MFI) for each labelled antibody was analysed on monocytes using Cell Quest (Becton Dickinson, San Diego, CA). We have previously shown that the fluorescent antibodies used do not demonstrate non-specific binding in this model 18 .…”

Section: Scientific Reports |mentioning

confidence: 73%

“…In order to study the molecular mechanisms underpinning monocyte impairment, we adopted the approach of isolating CD14 monocytes from whole blood of healthy volunteers and used a model of endotoxin tolerance similar to that of other groups 15,16 . Our experience with this model regarding the purity and time course of the suppressed cytokine response has been previously reported 17,18 . In isolated monocytes exposed to a low dose of LPS (10 ng/mL), there is a suppressed ability to produce TNF-α, IL-10 and IL-6 protein following an LPS challenge (100 ng/mL) (p < 0.05) when compared to the naïve monocyte not exposed to low dose LPS stimulation (Fig.…”

Section: Resultsmentioning

confidence: 95%

“…We adopted a model of impaired monocyte function using isolated primary human monocytes to represent the decreased cellular responsiveness seen in patients who are at very high risk. The present study builds on previous work that was used to select the time points studied 17,18 . The impaired monocytes in this model had a distinct profile based on cytokine and chemokine production with an AUC of 1.00, indicating that this impairment model profile predicted tolerant conditions in all cases.…”

Section: Discussionmentioning

confidence: 99%

“…However, importantly there is an incomplete understanding of the underlying signalling defects involved in suppression of these important host defence parameters. Our group recently showed that while IFN-γ could restore TNF-α production and monocyte HLA-DR expression, a short exposure of IκK-16 had differing modulatory effects including decreasing TNF-α production and PD-L1 expression while preserving IL-10 levels and CD14 expression 18 . The present study indicates that suppressed IκKα/β phosphorylation is one mechanism which contributes to a blunted cytokine and chemokine response.…”

Section: Discussionmentioning

confidence: 99%

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The role and function of IκKα/β in monocyte impairment

Galbraith

Gardner

Trainor

et al. 2020

Sci Rep

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Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/β, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/β complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naïve monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/β with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1β, TNF-β, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/β activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκKα/β is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/β function to restore monocyte function in this clinically important problem.

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Section: Scientific Reports |mentioning

confidence: 73%

Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The role and function of IκKα/β in monocyte impairment

Galbraith

Gardner

Trainor

et al. 2020

Sci Rep

Self Cite

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“…Repeated exposures to LPS induce ''endotoxin tolerance'' or anergy in macrophages and monocytes that renders these cells unresponsive to further stimulation. [5][6][7][8] This phenomenon is detrimental in patients with chronic infections or sepsis. It is also associated with reduced T-cell responses, possibly because of low HLA-DR expression.…”

mentioning

confidence: 99%

T-cell phenotypes are associated with serum IgE levels in Amish and Hutterite children

Hrusch

Stein

Gozdz

et al. 2019

Journal of Allergy and Clinical Immunology

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Tetramethylpyrazine Protects Blood-Spinal Cord Barrier Integrity by Modulating Microglia Polarization Through Activation of STAT3/SOCS3 and Inhibition of NF-кB Signaling Pathways in Experimental Autoimmune Encephalomyelitis Mice

Zhang

Gong

et al. 2020

Cell Mol Neurobiol

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We previously reported that tetramethylpyrazine (TMP) alleviates experimental autoimmune encephalomyelitis (EAE) by decreasing glia activation. Activated microglia has been shown to mediate blood-spinal cord barrier (BSCB) disruption, which is a primary and continuous pathological characteristic of multiple sclerosis (MS). Therefore, in this study, we further investigated whether TMP protects the BSCB integrity by inhibition of glia activation to alleviate EAE. Extravasation of evans blue was used to detect the BSCB disruption. Tumor necrosis factor-α (TNF-α)/interlukine-1β (IL-1β) and interlukine-4 (IL-4)/interlukine-10 (IL-10) were determined by enzyme-linked immunosorbent assay. BV2 glial cells stimulated by interferon-γ (IFN-γ) were co-cultured with human brain microvascular endothelial cells to investigate the effect of TMP on the BSCB disruption. Flow cytometry was used to analyze the microglia phenotype. Western blot was performed to reveal the signaling pathways involved in the microglia activation. In this study, most importantly, we found that TMP protects the BSCB integrity by modulating microglia polarization from M1 phenotype to M2 phenotype through activation of STAT3/SOCS3 and inhibition of NF-кB signaling pathways. Moreover, TMP significantly preserves the tight junction proteins, reduces the secretion of pro-inflammatory cytokines (TNF-α, IL-1β) and increases the secretion of anti-inflammatory cytokines (IL-4, IL-10) from IFN-γ-stimulated BV2 microglia cells. Consequently, protection of the BSCB integrity leads to alleviation of clinical symptoms and demyelination in EAE mice. Therefore, TMP might be an effective therapeutic agent for cerebral disorders with BBB or BSCB disruption, such as ischemic stroke, MS, and traumatic brain injury.

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The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes

Cited by 8 publications

References 38 publications

The role and function of IκKα/β in monocyte impairment

The role and function of IκKα/β in monocyte impairment

T-cell phenotypes are associated with serum IgE levels in Amish and Hutterite children

Tetramethylpyrazine Protects Blood-Spinal Cord Barrier Integrity by Modulating Microglia Polarization Through Activation of STAT3/SOCS3 and Inhibition of NF-кB Signaling Pathways in Experimental Autoimmune Encephalomyelitis Mice

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