Endotoxin-induced IL-6 promoter activation in skeletal muscle requires an NF-&amp;kappa;B site

Yeagley, David; Lang, Charles H.

doi:10.2147/ijicmr.s6690

Cited by 7 publications

(7 citation statements)

References 42 publications

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“…In C2C12 myocytes, NF-κB is necessary for IL-6 induction by LPS, and the ability of LPS to activate the IL-6 promoter is independent of the NF-IL6 and AP-1. Furthermore, LPS increases NF-κB activity by increasing the nuclear content of RelA, but not RelB 24 . In gastric epithelial cells, H. pylori induces IL-6 production through MAPK and NF-κB pathways 26 .…”

Section: Discussionmentioning

confidence: 92%

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GSK3β inhibition attenuates LPS-induced IL-6 expression in porcine adipocytes

Wang

2018

Sci Rep

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IL-6 is not only a proinflammatory cytokine associated with inflammatory responses but also a regulator on the energy and glucose metabolism in adipose tissue. Glycogen synthase kinase 3β (GSK3β) has fundamental roles in the regulation of pro- and anti-inflammatory cytokines production. However, the regulatory role for GSK3β in the pig inflammatory response in adipocytes remains unknown. We show here that SB216763 and LPS increased the phosphorylation of GSK3β (Ser9), and decreased the phosphorylation of GS (Ser641) in adipocytes. The activity of porcine GSK3β was inhibited by SB216763, an inhibitor of GSK3β, attenuated the production of IL-6 in LPS-stimulated adipocytes. Additionally, the essential core region of the pig IL-6 promoter located at −191 bp to −59 bp, and an NF-κBp65 element in this region was responsible for IL-6 promoter activity. The transcription activity of NF-κBp65 was activated by LPS stimulation, and the GSK3β inhibition repressed LPS-induced luciferase activity of the IL-6 promoter. Furthermore, LPS increased p65 binding to the NF-κB site, and GSK3β inhibition had no effect on the association of NF-κBp65 with IL-6 gene promoter after LPS treatment. These results demonstrate that GSK3β has important regulatory roles in the LPS-induced inflammatory response of IL-6 production in pig adipocytes.

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Section: Discussionmentioning

confidence: 92%

“…The IL-6 proximal promoter contains functional cis-regulatory elements, such as AP-1, SP1, NF-κB and C/EBPβ, contributing to the complex regulation of the IL6 gene 21 – 24 . Interestingly, the transcription factors which regulated the expression of IL-6 appear to be dependent on the cell types and the signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

GSK3β inhibition attenuates LPS-induced IL-6 expression in porcine adipocytes

Wang

2018

Sci Rep

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“…The IL-6 promoter contains multiple regulatory transcription factor elements [ 54 ]. Among these, NF-κB site (-73 to -64) in the IL-6 promoter was proposed to be necessary for IL-1 induced expression [ 55 ]. NF-κB is a family of transcription factors that are functional as dimeric complexes and is a known target of curcumin [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IL-6 Signaling Pathway by Curcumin in Uterine Decidual Cells

et al. 2015

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IL-6 is a multifunctional pro-inflammatory cytokine and has been implicated in many gestational disorders including preterm birth. Currently, there are no appropriate therapeutic interventions available to circumvent inflammatory-mediated gestational disorders. Therefore, the goal of this study was to identify a safe and effective pharmacological compound to counterbalance inflammatory responses in the uterus. Curcumin, a naturally-occuring polyphenolic compound, has been widely used in alternative medicine to treat inflammatory diseases. However, the anti-inflammatory effect of curcumin has not been explored in uterine decidual cells, a major source of IL-6. Therefore, we examined the effect of curcumin on IL-6 expression using two types of uterine decidual cells 1) HuF cells, primary human fibroblast cells obtained from the decidua parietalis; 2) UIII cells, a rodent non-transformed decidual cell line. Curcumin treatment completely abrogated the expression of IL-1β-induced IL-6 in these cells. Curcumin also strongly inhibited the expression of gp130, a critical molecule in IL-6 signaling, whereas expression of IL-6R and sIL-6R was not affected. Curcumin also inhibited phosphorylation and nuclear localization of STAT3, a well-known downstream mediator of IL-6 signaling. Furthermore, curcumin attenuated IL-1β-induced IL-6 promoter reporter activity suggesting transcriptional regulation. To further understand whether NF-ҡB is involved in this inhibition, we examined the effect of curcumin on the expression of p50 and p65 subunits of NF-ҡB in decidual cells. Expression of IL-1β-induced p50 mRNA was repressed by curcumin while p65 mRNA was not affected. However, curcumin treatment dramatically inhibited both p50 and p65 protein levels and prevented its nuclear localization. This effect is at least partly mediated through the deactivation of IKK, since IL-1β-induced IKKα/β phosphorylation is decreased upon curcumin treatment. Our results not only revealed molecular mechanisms underlying curcumin action in uterine decidual cells but also suggest that this compound may have therapeutic potential for the prevention of inflammation-mediated preterm birth and other gestational disorders.

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“…A 3D tissue construct more accurately represents the cells in an in vivo environment and is hence a better model to study topics like disease physiology and drug discovery than a more traditional 2D cell culture. , To investigate the compatibility of dRAPPID with advanced cell culturing systems, we stimulated a human 3D muscle tissue model with lipopolysaccharide (LPS) and measured the corresponding IL-6 secretion of the muscle cells with dRAPPID. LPS is an endotoxin that stimulates the expression of proinflammatory cytokines in many different types of tissues and cells, including skeletal muscle cells. , We fabricated the 3D muscle models as described previously and subsequently stimulated them with LPS . Culture medium samples (10 μL) were removed after 2, 4, and 24 h of LPS stimulation (Figure c).…”

Section: Resultsmentioning

confidence: 99%

Integrated Bioluminescent Immunoassays for High-Throughput Sampling and Continuous Monitoring of Cytokines

van Aalen,

Rosier,

Jansen

et al. 2023

Anal. Chem.

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Immunoassays show great potential for the detection of low levels of cytokines, due to their high sensitivity and excellent specificity. There is a particular demand for biosensors that enable both high-throughput screening and continuous monitoring of clinically relevant cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα). To this end, we here introduce a novel bioluminescent immunoassay based on the ratiometric plug-and-play immunodiagnostics (RAPPID) platform, with an improved intrinsic signal-to-background and an >80-fold increase in the luminescent signal. The new dRAPPID assay, comprising a dimeric protein G adapter connected via a semiflexible linker, was applied to detect the secretion of IL-6 by breast carcinoma cells upon TNFα stimulation and the production of low concentrations of IL-6 (∼18 pM) in an endotoxin-stimulated human 3D muscle tissue model. Moreover, we integrated the dRAPPID assay in a newly developed microfluidic device for the simultaneous and continuous monitoring of changes in IL-6 and TNFα in the low-nanomolar range. The luminescence-based read-out and the homogeneous nature of the dRAPPID platform allowed for detection with a simple measurement setup, consisting of a digital camera and a light-sealed box. This permits the usage of the continuous dRAPPID monitoring chip at the point of need, without the requirement for complex or expensive detection techniques.

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Endotoxin-induced IL-6 promoter activation in skeletal muscle requires an NF-κB site

Cited by 7 publications

References 42 publications

GSK3β inhibition attenuates LPS-induced IL-6 expression in porcine adipocytes

GSK3β inhibition attenuates LPS-induced IL-6 expression in porcine adipocytes

Inhibition of IL-6 Signaling Pathway by Curcumin in Uterine Decidual Cells

Integrated Bioluminescent Immunoassays for High-Throughput Sampling and Continuous Monitoring of Cytokines

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