Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive memory loss. Magnolol (MN), the main active ingredient of Magnolia officinalis, possesses anti-AD effects in several experimental models of AD. In this study, we aimed to explore whether MN could ameliorate the cognitive deficits in TgCRND8 transgenic mice and to elucidate its molecular mechanisms. Male TgCRND8 mice were orally administered with MN (20 and 40 mg/kg) daily for 4 consecutive months, followed by assessing the spatial learning and memory functions using the open-field, radial arm maze, and novel object recognition tests. The results demonstrated that MN (20 and 40 mg/kg) could markedly ameliorate the cognitive deficits in TgCRND8 mice. In addition, MN significantly increased the expression of postsynaptic density protein 93 (PSD93), PSD-95, synapsin-1, synaptotagmin-1, synaptophysin (SYN), and interleukin-10 (IL-10), while markedly reduced the protein levels of tumor necrosis factor alpha (TNF-α), IL-6, IL-1β, Aβ40, and Aβ42, and modulated the amyloid precursor protein (APP) processing and phosphorylation. Immunofluorescence showed that MN significantly suppressed the activation of microglia (Iba-1) and astrocytes (GFAP) in the hippocampus and cerebral cortex of TgCRND8 mice. Mechanistic studies revealed that MN could significantly increase the ratios of p-GSK-3β (Ser9)/GSK-3β, p-Akt (Ser473)/Akt, and p-NF-κB p65/NF-κB p65. These findings indicate that MN exerted cognitive deficits improving effects via suppressing neuroinflammation, amyloid pathology, and synaptic dysfunction through regulating the PI3K/Akt/GSK-3β and NF-κB pathways, suggesting that MN is a promising naturally occurring polyphenol worthy of further developing into a therapeutic agent for AD treatment.

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ICOSLG-mediated regulatory T cell expansion and IL-10 production promote progression of glioblastoma

Neuro-Oncology ◽

10.1093/neuonc/noz204 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ryoichi Iwata ◽

Joo Hyoung Lee ◽

Mikio Hayashi ◽

Umberto Dianzani ◽

Kohei Ofune ◽

...

Keyword(s):

T Cell ◽

Molecular Mechanisms ◽

Interleukin 10 ◽

Dependent Manner ◽

Gene Encoding ◽

Checkpoint Proteins ◽

Underlying Mechanisms ◽

Immune Checkpoint Proteins ◽

Factor Α ◽

Regulatory Ligands

Abstract Background Targeting immune checkpoint proteins has recently gained substantial attention due to the dramatic success of this strategy in clinical trials for some cancers. Inducible T-cell co-stimulator ligand (ICOSLG) is a member of the B7 family of immune regulatory ligands, expression of which in cancer is implicated in disease progression due to regulation of anti-tumor adaptive immunity. Although aberrant ICOSLG expression has been reported in glioma cells, the underlying mechanisms that promote glioblastoma (GBM) progression remain elusive. Methods Here, we investigated a causal role for ICOSLG in GBM progression by analyzing ICOSLG expression in both human glioma tissues and patient-derived GBM sphere cells (GSCs). We further examined its immune modulatory effects and the underlying molecular mechanisms. Results Bioinformatics analysis and GBM tissue microarray showed that upregulation of ICOSLG expression was associated with poor prognosis in patients with GBM. ICOSLG expression was upregulated preferentially in mesenchymal GSCs but not in proneural GSCs in a tumor necrosis factor-α-/NF-ĸB-dependent manner. Furthermore, ICOSLG expression by mesenchymal GSCs promoted expansion of T cells that produced interleukin-10. Knockdown of the gene encoding ICOSLG markedly reduced GBM tumor growth in immune competent mice, with a concomitant downregulation of interleukin-10 levels in the tumor microenvironment. Conclusions Inhibition of the ICOSLG-ICOS axis in GBM may provide a promising immunotherapeutic approach for suppressing a subset of GBM with an elevated mesenchymal signature.

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STAT3 regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells

Blood ◽

10.1182/blood-2004-04-1309 ◽

2005 ◽

Vol 105 (2) ◽

pp. 689-696 ◽

Cited By ~ 108

Author(s):

Frank Hoentjen ◽

R. Balfour Sartor ◽

Michitaka Ozaki ◽

Christian Jobin

Keyword(s):

Gene Expression ◽

Dendritic Cells ◽

Molecular Mechanisms ◽

Intestinal Inflammation ◽

Nuclear Translocation ◽

Green Fluorescence Protein ◽

Interleukin 10 ◽

Mrna Accumulation ◽

Stat3 Phosphorylation ◽

Regulatory Effects

Abstract Interleukin-10-deficient (IL-10-/-) mice develop an IL-12-mediated intestinal inflammation in the absence of endogenous IL-10. The molecular mechanisms of the dysregulated IL-12 responses in IL-10-/- mice are poorly understood. In this study, we investigated the role of nuclear factor-κ B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) in lipopolysaccharide (LPS)-induced IL-12p40 gene expression in bone marrow derived-dendritic cells (BMDCs) isolated from wild-type (WT) and IL-10-/- mice. We report higher IL-12p40 mRNA accumulation and protein secretion in LPS-stimulated BMDCs isolated from IL-10-/- compared with WT mice. LPS-induced NF-κB signaling is similar in IL-10-/- and WT BMDCs as measured by IκBα phosphorylation and degradation, RelA phosphorylation and nuclear translocation, and NF-κB transcriptional activity, with no down-regulatory effects of exogenous IL-10. Chromatin immunoprecipitation demonstrated enhanced NF-κB (cRel, RelA) binding to the IL-12p40 promoter in IL-10-/- but not WT BMDCs. Interestingly, LPS induced STAT3 phosphorylation in WT but not IL-10-/- BMDCs, a process blocked by IL-10 receptor blocking antibody. Adenoviral gene delivery of a constitutively active STAT3 but not control green fluorescence protein (GFP) virus blocked LPS-induced IL-12p40 gene expression and cRel recruitment to the IL-12p40 promoter. In conclusion, dysregulated LPS-induced IL-12p40 gene expression in IL-10-/- mice is due to enhanced NF-κB recruitment to the IL-12p40 promoter in the absence of activated STAT3.

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Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820466116 ◽

2019 ◽

Vol 116 (21) ◽

pp. 10557-10562 ◽

Cited By ~ 19

Author(s):

Zhoumou Chen ◽

Timothy M. Doyle ◽

Livio Luongo ◽

Tally M. Largent-Milnes ◽

Luigino Antonio Giancotti ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Molecular Mechanisms ◽

Interleukin 10 ◽

Sphingolipid Metabolism ◽

Receptor Subtype ◽

Endogenous Opioid ◽

Major Health Problem ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

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The molecular and cellular basis of corticosteroid resistance

Journal of Endocrinology ◽

10.1677/joe.0.1790301 ◽

2003 ◽

Vol 179 (3) ◽

pp. 301-310 ◽

Cited By ~ 20

Author(s):

IC Chikanza ◽

D Kozaci ◽

Y Chernajovsky

Keyword(s):

Rheumatoid Arthritis ◽

Peripheral Blood ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Intracellular Signalling ◽

Signalling Pathways ◽

Peripheral Blood Mononuclear ◽

Intracellular Signalling Pathways ◽

Nf Kappab

Corticosteroids (CS) can modulate gene expression and are often used to treat a range of immunological and inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. However, a proportion of patients fail to show an adequate response. On this basis patients have been subdivided into CS-sensitive (SS) and -resistant (SR) subgroups. The ability of CS to inhibit peripheral blood T cell proliferation in vitro has also been used similarly. In rheumatoid arthritis (RA), the in vitro-defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms responsible for this observation are unknown but they appear to involve a number of known molecular events related to the described mechanisms of action of CS. These include alterations in the functional status of CS receptor-alpha, perturbations of the cytokine and hormonal milieu and intracellular signalling pathways. Peripheral blood mononuclear cells (MNCs) from SR significantly overexpress activated NF-kappaB. In vitro, CS fail to significantly inhibit concanavalin A (conA)-induced NF-kappaB activation in MNCs from SR RA patients. The alterations in the intracellular signalling pathways may explain in part our observations seen in SR RA subjects, CS fail to significantly inhibit conA-induced interleukin (IL)-2 and IL-4 secretion and lipopolysaccharide-induced IL-8 and IL-1beta secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8 and IL-1beta in RA patients. In asthma, CS fail to induce L10 in SR asthma patients. Other molecular mechanisms such as enhanced AP-1 expression and alterations in the MAP kinase pathway are most likely to be involved too and we are currently investigating such possibilities. A full understanding of the molecular basis of SR will lead to the development of more rational therapeutic strategies.

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IL-10 Treatment Is Associated with Prohibitin Expression in the Crohn’s Disease Intestinal Fibrosis Mouse Model

Mediators of Inflammation ◽

10.1155/2013/617145 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

C. Yuan ◽

W.-X. Chen ◽

J.-S. Zhu ◽

N.-W. Chen ◽

Y.-M. Lu ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Mouse Model ◽

Molecular Mechanisms ◽

Quantitative Polymerase Chain Reaction ◽

Interleukin 10 ◽

Colon Tissue ◽

Intestinal Fibrosis ◽

Murine Colitis ◽

Inflammatory Bowel

Prohibitin, which can inhibit oxidative stress and mitochondrial dysfunction, has been shown to have significant anti-inflammatory activities. Here, we investigate the effects of altering prohibitin levels in affected tissues in the interleukin-10 knockout (IL-10KO) mouse model with intestinal fibrosis. The aim of this study is to investigate the effects of IL-10 on prohibitin and the role of prohibitin in intestinal fibrosis of murine colitis. After the mice were treated with IL-10, prohibitin expression and localization were evaluated in IL-10KO and wild-type (WT, 129/SvEv) mice. The colon tissue was then investigated and the potential pathogenic molecular mechanisms were further studied. Fluorescence-based quantitative polymerase chain reaction (FQ-PCR) and immunohistochemistry assays revealed a significant upregulation of prohibitin with IL-10 treatment. Furthermore, IL-10 decreases inflammatory cytokines and TGF-β1 in the IL-10KO model of Crohn’s disease and demonstrates a promising trend in decreasing tissue fibrosis. In conclusion, we hypothesize that IL-10 treatment is associated with increased prohibitin and would decrease inflammation and fibrosis in an animal model of Crohn’s disease. Interestingly, prohibitin may be a potential target for intestinal fibrosis associated with inflammatory bowel disease (IBD).

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Revisiting the Hygiene Hypothesis in the Context of Autoimmunity

Frontiers in Immunology ◽

10.3389/fimmu.2020.615192 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jean-François Bach

Keyword(s):

Molecular Mechanisms ◽

Epidemiological Data ◽

Allergic Diseases ◽

Hygiene Hypothesis ◽

Interleukin 10 ◽

Major Question ◽

Important Place ◽

Immunoregulatory Cytokines ◽

Underlying Mechanisms

Initially described for allergic diseases, the hygiene hypothesis was extended to autoimmune diseases in the early 2000s. A historical overview allows appreciation of the development of this concept over the last two decades and its discussion in the context of evolution. While the epidemiological data are convergent, with a few exceptions, the underlying mechanisms are multiple and complex. A major question is to determine what is the respective role of pathogens, bacteria, viruses, and parasites, versus commensals. The role of the intestinal microbiota has elicited much interest, but is it a cause or a consequence of autoimmune-mediated inflammation? Our hypothesis is that both pathogens and commensals intervene. Another question is to dissect what are the underlying cellular and molecular mechanisms. The role of immunoregulatory cytokines, in particular interleukin-10 and TGF beta is probably essential. An important place should also be given to ligands of innate immunity receptors present in bacteria, viruses or parasites acting independently of their immunogenicity. The role of Toll-Like Receptor (TLR) ligands is well documented including via TLR ligand desensitization.

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Activin A correlates with the worst outcomes in COVID-19 patients, and can be induced by cytokines via the IKK/NF-kappa B pathway

10.1101/2021.02.04.429815 ◽

2021 ◽

Author(s):

Megan McAleavy ◽

Qian Zhang ◽

Jianing Xu ◽

Li Pan ◽

Matthew Wakai ◽

...

Keyword(s):

Molecular Mechanisms ◽

Activin A ◽

Severe Form ◽

Acute Respiratory Disease ◽

Nf Kappa B ◽

Sample Median ◽

Longitudinal Outcomes ◽

All Cause Mortality ◽

Patients At Risk ◽

Nf Kappab

SummaryA fraction of COVID-19 patients develop the most severe form, characterized by Acute Respiratory Disease Syndrome (ARDS). The molecular mechanisms causing COVID-19-induced ARDS have yet to be defined, though many studies have documented an increase in cytokines known as a “cytokine storm.” Here, we demonstrate that cytokines that activate the NF-kappaB pathway can induce Activin A and its downstream marker, FLRG. In hospitalized COVID-19 patients elevated Activin A/FLRG at baseline were predictive of the most severe longitudinal outcomes of COVID-19, including the need for mechanical ventilation, lack of clinical improvement and all-cause mortality. Patients with Activin A/FLRG above the sample median were 2.6/2.9 times more likely to die, relative to patients with levels below the sample median, respectively. The study indicates high levels of Activin A and FLRG put patients at risk of ARDS, and blockade of Activin A may be beneficial in treating COVID-19 patients experiencing ARDS.

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Indoleamine 2,3-dioxgenase-transfected mesenchymal stem cells suppress heart allograft rejection by increasing the production and activity of dendritic cells and regulatory T cells

Journal of Investigative Medicine ◽

10.1136/jim-2019-001160 ◽

2019 ◽

Vol 68 (3) ◽

pp. 728-737 ◽

Cited By ~ 2

Author(s):

Ji-Gang He ◽

Bei-Bei Li ◽

Liang Zhou ◽

Dan Yan ◽

Qiao-Li Xie ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Mesenchymal Stem Cells ◽

Dendritic Cells ◽

Transforming Growth Factor Beta ◽

Allograft Rejection ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Interleukin 10 ◽

Heart Allograft

Expression of indoleamine 2,3-dioxygenase (IDO) in mesenchymal stem cells (MSC) is thought to contribute to MSC-mediated immunosuppression. A lentiviral-based transgenic system was used to generate bone marrow stem cells (BMSC) which stably expressed IDO (IDO-BMSCs). Coculture of IDO-BMSCs with dendritic cells (DC) or T cells was used to evaluate the immunomodulatory effect of IDO-BMSCs. A heterotopic heart transplant model in rats was used to evaluate allograft rejection after IDO-BMSC treatment. Mechanisms of IDO-BMSC-mediated immunosuppression were investigated by evaluating levels of proinflammatory and anti-inflammatory cytokines, and production of Tregs. A significant decrease in DC marker-positive cells and a significant increase in Tregs were observed in IDO-BMSC cocultured. Treatment of transplanted rats with IDO-BMSCs was associated with significantly prolonged graft survival. Compared with the control groups, transplanted animals treated with IDO-BMSCs had a (1) significantly higher ejection fraction and fractional shortening, (2) significantly lower expression of CD86, CD80, and MHCII, and significantly higher expression in CD274, and Tregs, and (3) significantly higher levels of interleukin-10 (IL-10), transforming growth factor beta-1 (TGF-β1), TGF-β2, and TGF-β3, and significantly lower levels of IL-2 and interferon gamma. Our results expand our understanding of the molecular mechanisms underlying suppression of heart allograft rejection via IDO-expressing BMSCs.

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Protective effects of combined micronutrients on islet β-cells of streptozotocin-induced diabetic mice

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.79.2.104 ◽

2009 ◽

Vol 79 (2) ◽

pp. 104-116 ◽

Cited By ~ 3

Author(s):

Ying Chang ◽

Gui-Zhen Zhang ◽

Song-Lan Piao ◽

Shen Gao ◽

De-Ming Zheng ◽

...

Keyword(s):

Pancreatic Islets ◽

Molecular Mechanisms ◽

Interleukin 10 ◽

Protective Effects ◽

Diabetic Mice ◽

T Helper ◽

T Helper 1 ◽

Β Cells ◽

High Blood Glucose ◽

Glucose Levels

There is a tendency for the incidence of diabetes in a population to increase with an improvement in living standards. This would imply the involvement of nutritional factors in the development of diabetes, and so nutritional considerations could be a key aspect in the research and development of an effective remedy for diabetes. In this study, combined micronutrients (selenium, vitamin E, vanadium, and chromium) were orally supplemented to streptozotocin-induced diabetic mice. Results showed that combined micronutrients could decrease the high blood glucose levels (p<0.05 or p<0.01) of diabetic mice. The protective effects of combined micronutrients on structures of β-cells in pancreatic islets of diabetic mice were observed histopathologically and ultrastructurally. In addition, the supplementation of combined micronutrients increased insulin expression by β-cells in pancreatic islets of diabetic mice at both translational and transcriptional levels. The immune molecular mechanisms involved were preliminarily regarded as downregulation of the expression of pathogenic T-helper 1 lymphocyte (Th1) cytokine tumor necrosis factor-α (TNF-α) (p<0.01) along with upregulation of the expression of protective T-helper 2 lymphocyte Th2 cytokine interleukin 10 (IL-10) (p<0.01) which ameliorates the Th1/Th2 imbalance in diabetes. In conclusion, supplementation of combined micronutrients to diabetic mice could effectively improve disordered glucose metabolism, protect islet structures, and improve the function of β-cells in pancreatic islets, which are affected by differential regulation of the expression of Th1/Th2 cytokines involved in the pathogenesis of diabetes.

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