Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation

Gumá, Mónica; Stepniak, Dariusz; Shaked, Helena; Spehlmann, Martina E.; Shenouda, Steve; Cheroutre, Hilde; Vicente-Suarez, Ildelfonso; Eckmann, Lars; Kagnoff, Martin F.; Karin, Michael

doi:10.1084/jem.20110242

Cited by 139 publications

(107 citation statements)

References 51 publications

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“…A recent study demonstrated that both MAPK and NF-κB signals, which are key regulators in intestinal inflammation, have immunostimulatory properties; they induce the activation and cytokine secretion in various immune cells, thereby driving intestinal tissue damage via inflammatory cytokines [25, 26]. Furthermore, the NF-κB signal does not trigger excessive inflammation unless it is accompanied by MAPK signaling activation [27]. Thus, effective regulation of Tollip, MAPK and NF-κB signals are one important step for new drug development for IBD.…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells

Byun

Kim

Sung

et al. 2018

Cell Physiol Biochem

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Background/Aims: Inflammatory bowel disease (IBD) is a condition that involves chronic inflammation in all or part of the digestive tract. Often painful and debilitating, IBD can lead to life-threatening complications and increase the risk for colon cancer. In this study, we investigated the epigallocatechin-3-gallate (EGCG) mediated anti-inflammation response in lipopolysaccharide (LPS)-stimulated human colorectal cells through the negative regulator of Toll-like receptor (TLR) signaling. Methods: human intestinal epithelial cells (HT-29) were used in all experiments. Cell cytotoxicity and nitric oxide (NO) were evaluated by WST-1 and the Griess reagent. Western blot analysis and ELISA were used to determine inflammatory mediators and 67-kDa laminin receptor (67LR)-mediated Tollip signaling pathways. Results: Treatment of EGCG and LPS did not affect the cytotoxicity in HT-29 cells. LPS treatment dose-dependently increased the pro-inflammatory cytokine, such as interleukin (IL)-8, whereas EGCG significantly reduced the LPS-stimulated IL-8 production. Additionally, EGCG treatment markedly increased the Toll-interacting protein (Tollip) expression, which negatively regulates the TLR signaling in a dose and time-dependent manner. In particular, in the result from an RNA interference-mediated assay, our finding showed that silencing of Tollip resulted in abrogation of the inhibitory action of EGCG on LPS-induced production of pro-inflammatory mediators (inducible nitric oxide synthase-mediated NO/COX2, and IL-8) and activation of MAPKs and NF-κB signaling pathways. Interestingly, we also found that Tollip expression induced by EGCG could be modulated through 67LR expressed on the surface of HT-29 cells. Conclusions: Our novel finding indicates that 67LR and Tollip signaling activated by EGCG treatment is essential for inhibition of inflammation in human intestinal epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells

Byun

Kim

Sung

et al. 2018

Cell Physiol Biochem

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“…Intestinal permeability and gut barrier function were measured using the FITC-labeled dextran method as previously described 56 and by measuring fecal albumin. Fecal albumin measurements were performed with dried fecal pellets using the Mouse Albumin ELISA Quantitation Set obtained from Bethyl Laboratories (Montgomery, TX, USA) according to manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

A gp130–Src–YAP module links inflammation to epithelial regeneration

Taniguchi

Grivennikov

et al. 2015

Nature

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539

532

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Summary Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members whose expression is elevated in many diseases, including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). We show that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the classic gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signaling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated upon receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signaling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.

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“…The transcription factor NFκB is redox-sensitive, that is, responsive to H 2 O 2 modulation, and is also stimulated by proinflammatory cytokines such as TNFα and IL-1β (Li & Verma, 2002). Persistent activation of NFκB engages MAPK activation (Guma et al ., 2011), and stress-responsive JNK signaling was especially involved in insulin resistance and inflammation (Han et al ., 2013) and in aging and neurodegenerative diseases (Mehan et al ., 2011; Jiang et al ., 2013). Astrocytes surround neurons and synapses, and the question arises on how the inflammatory responses generated by astrocytes propagate to neurons and affect their functions.…”

Section: Introductionmentioning

confidence: 99%

Astrocytic metabolic and inflammatory changes as a function of age

2014

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This study examines age-dependent metabolic-inflammatory axis in primary astrocytes isolated from brain cortices of 7-, 13-, and 18-month-old Sprague–Dawley male rats. Astrocytes showed an age-dependent increase in mitochondrial oxidative metabolism respiring on glucose and/or pyruvate substrates; this increase in mitochondrial oxidative metabolism was accompanied by increases in COX3/18SrDNA values, thus suggesting an enhanced mitochondrial biogenesis. Enhanced mitochondrial respiration in astrocytes limits the substrate supply from astrocytes to neurons; this may be viewed as an adaptive mechanism to altered cellular inflammatory–redox environment with age. These metabolic changes were associated with an age-dependent increase in hydrogen peroxide generation (largely ascribed to an enhanced expression of NOX2) and NFκB signaling in the cytosol as well as its translocation to the nucleus. Astrocytes also displayed augmented responses with age to inflammatory cytokines, IL-1β, and TNFα. Activation of NFκB signaling resulted in increased expression of nitric oxide synthase 2 (inducible nitric oxide synthase), leading to elevated nitric oxide production. IL-1β and TNFα treatment stimulated mitochondrial oxidative metabolism and mitochondrial biogenesis in astrocytes. It may be surmised that increased mitochondrial aerobic metabolism and inflammatory responses are interconnected and support the functionality switch of astrocytes, from neurotrophic to neurotoxic with age.

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Constitutive intestinal NF-κB does not trigger destructive inflammation unless accompanied by MAPK activation

Abstract: Constitutive NF-κB activation in IECs induces inflammatory cytokines and chemokines in the lamina propria, but does not result in overt tissue damage unless acute inflammatory insults are present, causing TNF-dependent destruction and barrier disruption.

Cited by 139 publications

References 51 publications

Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells

Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide-Stimulated Human Intestinal Epithelial Cells

A gp130–Src–YAP module links inflammation to epithelial regeneration

Astrocytic metabolic and inflammatory changes as a function of age

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