scholarly journals Nuclear factor κB pathway and interleukin-6 are affected in eutopic endometrium of women with endometriosis

Reproduction ◽  
2009 ◽  
Vol 137 (4) ◽  
pp. 727-737 ◽  
Author(s):  
Carlos Ponce ◽  
Marisa Torres ◽  
Carolina Galleguillos ◽  
Hugo Sovino ◽  
M Angélica Boric ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Secretory Phase ◽  
Normal Endometrium ◽  
Eutopic Endometrium ◽  
Iκb Kinase ◽  
Nfkb Pathway ◽  
Late Secretory Phase

In order to investigate the role of the nuclear factor κB (NFKB) pathway on gene expression in the eutopic endometrium in endometriosis, and in particular of interleukin-6 (IL6), we evaluated RELA, IκB kinase (CHUK), NFKBIA and IL6 expressions and NFKB DNA binding in eutopic endometrium from women with endometriosis. Eutopic endometrium was obtained from 37 women with endometriosis and 42 fertile women during laparoscopy. We analysed RELA, CHUK, NFKBIA and IL6 mRNA levels (RT-PCR); RELA, CHUK and NFKBIA proteins and p-NFKBIA/NFKBIA ratio (western blot); and NFKB binding (DNA shift assay) and IL6 concentration (ELISA) in endometrial explants. Our results indicate that mRNA and cytoplasmic proteins of RELA and CHUK exhibit constant levels in normal endometrium during the menstrual cycle. A dramatic increase (P<0.05) in NFKBIA mRNA expression, RELA nuclear presence and the mRNA and the protein of IL6 during late secretory phase was also observed in this tissue. By contrast, in eutopic endometrium from endometriosis patients, a decrease (P<0.05) in IL6 mRNA and protein (61%), NFKBIA mRNA (46%), p-NFKBIA/NFKBIA ratio (42%), RELA nuclear stromal (68%) and CHUK (48%) proteins were found exclusively during the late secretory phase compared with normal endometrium. In conclusion, the canonical activation of NFKB pathway is deregulated and may have reduced transcriptional function affecting NFKBIA and IL6 expression, genes related local proinflammatory processes. These molecular alterations observed during the late secretory phase in eutopic endometrium from endometriosis patients constitute a NFKB system dysfunction, suggesting that NFKB could be an important factor in endometriosis aetiology.

scholarly journals Central Administration of Resveratrol Improves Diet-Induced Diabetes

Endocrinology ◽  
2009 ◽  
Vol 150 (12) ◽  
pp. 5326-5333 ◽  
Author(s):  
Giorgio Ramadori ◽  
Laurent Gautron ◽  
Teppei Fujikawa ◽  
Claudia R. Vianna ◽  
Joel K. Elmquist ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Central Administration ◽  
Beneficial Effects ◽  
Intracerebroventricular Infusion ◽  
Iκb Kinase

Abstract Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-κB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-κB α and IκB kinase β mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.

Inhibitor of nuclear factor-κB induction by cAMP antagonizes interleukin-1-induced human macrophage-colony-stimulating-factor expression

2001 ◽  
Vol 356 (2) ◽  
pp. 525-530 ◽  
Author(s):  
Pisate J. KAMTHONG ◽  
Ming-chi WU
Keyword(s):  
Nuclear Factor Κb ◽  
Human Macrophage ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Colony Stimulating Factor ◽  
Dibutyryl Camp ◽  
Iκb Kinase ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

We have recently reported that interleukin-1α (IL-1α) can induce human macrophage colony-stimulating factor (M-CSF) expression through nuclear factor κB (NF-κB) activation, and treatment of human pancreatic MIA PaCa-2 cancer cells with forskolin or cAMP attenuated the NF-κB activation as well as M-CSF expression. In this study, we have further investigated the mechanism of cAMP attenuation. MIA PaCa-2 cells were incubated with forskolin or dibutyryl-cAMP and then stimulated with IL-1 for 1h. Cell lysates were immunoprecipitated by anti-inhibitory κB (IκB) kinase-β (IKKβ) antibody and the immune complex assayed for kinase activity using recombinant inhibitor of NF-κB (IκBα) as substrate. The levels of IKKβ in the respective cellular proteins were measured by subsequent Western blot. The results show that the level of IKK protein remains constant in the presence of cAMP, forskolin and/or IL-1, whereas IKK activity was robustly stimulated by IL-1. Nonetheless, dibutyryl-cAMP or forskolin did not affect the IKK activation induced by IL-1. This experiment suggests that elevated cAMP has no effect on IKK activity. IκBα protein level decreased markedly in IL-1-treated cells compared with the untreated. By contrast, cells treated with cAMP or forskolin possessed discernibly higher IκBα levels. In addition, we observed that forskolin potentiated and prolonged the IL-1-induced IκBα mRNA levels, whereas it did not stabilize the IκBα mRNA message. Wholly, these studies indicate that elevated cAMP antagonizes IL-1-induced M-CSF transcription by up-regulating IκBα gene induction and its consequent attenuation of NF-κB activation.

Arsenite inhibits interleukin-6 production in human intestinal epithelial cells by down-regulating nuclear factor-κB activity

2002 ◽  
Vol 103 (4) ◽  
pp. 381-390 ◽  
Author(s):  
Dan D. HERSHKO ◽  
Bruce W. ROBB ◽  
Eric S. HUNGNESS ◽  
Guangju LUO ◽  
Xialing GUO ◽  
...  
Keyword(s):  
Dna Binding ◽  
Interleukin 6 ◽  
Sodium Arsenite ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Binding Activity ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Dna Binding Activity

Previous studies have suggested that the production of interleukin-6 (IL-6) is increased in the intestinal mucosa during inflammation, and that nuclear factor-κB (NF-κB) is an important regulator of the IL-6 gene in the enterocyte. We tested the hypothesis that sodium arsenite inhibits IL-6 production in stimulated enterocytes and that this effect of arsenite is caused by down-regulation of NF-κB activity. Cultured Caco-2 cells were treated with sodium arsenite and were then stimulated with IL-1β. IL-6 production and gene expression were determined by ELISA and reverse transcriptase–PCR respectively. NF-κB DNA binding activity was determined by electrophoretic mobility shift assay. IL-1β increased NF-κB DNA binding activity, IL-6 mRNA levels and IL-6 production. These effects of IL-1β were inhibited by treatment of the cells with sodium arsenite in a dose- and time-dependent fashion. When cells were transfected with a plasmid expressing the p65 subunit of NF-κB, the inhibitory effect of sodium arsenite on NF-κB activity and IL-6 production was blunted. These results suggest that sodium arsenite inhibits IL-6 production in enterocytes subjected to an inflammatory stimulus, and that this effect, at least in part, reflects down-regulated NF-κB activity.

scholarly journals Immunohistochemical study of the ubiquitin - nuclear factor-ΚB pathway in the endometrium of the baboon (Papio anubis) with and without endometriosis

2010 ◽  
Vol 22 (7) ◽  
pp. 1118 ◽  
Author(s):  
Romina S. Ilad ◽  
Steven D. Fleming ◽  
Christopher R. Murphy ◽  
Asgerally T. Fazleabas
Keyword(s):  
Menstrual Cycle ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Papio Anubis ◽  
Eutopic Endometrium ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Glandular Cells ◽  
Human Primate ◽  
Ectopic Endometrium

The aim of the present study was to conduct a semiquantitative immunohistochemical investigation into the levels of intermediary proteins within the nuclear factor (NF)-κB pathway throughout the menstrual cycle in a non-human primate, namely the baboon (Papio anubis), with and without endometriosis. Formalin-fixed eutopic (n = 2–4) and ectopic (n = 6–7) endometrial tissues from baboons at the mid-luteal phase were embedded in paraffin and examined for NF-κB pathway components (i.e. IκB kinase (IKK) α, IKKβ, phosphorylated (phospho-) IκBα and phospho-NF-κB p65 subunit), ubiquitin, 19S proteasome and the NF-κB activator tumour necrosis factor (TNF)-α. Similarly, endometrial tissues from baboons at the late follicular, mid-luteal and menses phase (n = 2–4) were investigated to determine the levels of these proteins throughout the menstrual cycle. Cytoplasmic stromal IKKα and glandular 19S proteasome immunostaining was elevated in the ectopic endometrium, whereas levels of ubiquitin, phospho-p65, IKKβ, TNF-α and nuclear 19S proteasome were similar in the eutopic and ectopic endometrium. A significant decrease in phospho-IκBα nuclear immunostaining was observed within glandular cells of the ectopic endometrium. In the eutopic endometrium, IKKα, ubiquitin and 19S proteasome immunostaining was elevated in different phases of the menstrual cycle, whereas levels of phospho-p65, IKKβ, phospho-IκBα and TNF-α remained unchanged. We have demonstrated that, in the baboon endometriosis model, levels of IKKα immunostaining are elevated, whereas those of phospho-IκBα are reduced, consistent with the hypothesis that excessive NF-κB activity plays a role in reducing ectopic endometrial apoptosis, which contributes to the pathophysiology of endometriosis. Further studies are required to confirm a causal association between elevated IKKα levels and reduced endometrial apoptosis.

scholarly journals Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1301-1307 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Pei-Xuan Wang ◽  
Kristal J. Aaron ◽  
Kolitha Basnayake ◽  
Paul W. Sanders
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Phosphorylation ◽  
Renal Injury ◽  
Src Kinase ◽  
Nuclear Factor Κb ◽  
Light Chains ◽  
Nuclear Factor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Renal Epithelial Cells ◽  
Iκb Kinase

Abstract One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells. Human proximal tubule epithelial cells exposed to 3 different human monoclonal FLCs demonstrated Src kinase–dependent activation of the NF-κB pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of κB kinases (IKKs) IKKα and IKKβ and a concomitant increase in inhibitor of κB (IκB) kinase activity in cell lysates were observed. Time-dependent, Src kinase–dependent increases in serine and tyrosine phosphorylation of IκBα and NF-κB activity were also demonstrated. Proteasome inhibition partially blocked FLC-induced MCP-1 production. These findings fit into a paradigm characterized by FLC-induced redox-signaling events that activated the canonical and atypical (IKK-independent) NF-κB pathways to promote a proinflammatory, profibrotic renal environment.

scholarly journals Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

2005 ◽  
Vol 25 (10) ◽  
pp. 1301-1311 ◽  
Author(s):  
Yun S Song ◽  
Yong-Sun Lee ◽  
Pak H Chan
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Dna Array ◽  
Wild Type ◽  
Iκb Kinase ◽  
Transient Focal Cerebral Ischemia ◽  
Ikk Complex ◽  
In The Wild

Nuclear factor-κB (NF-κB) has a central role in coordinating the expression of a wide variety of genes that control cerebral ischemia. Although there has been intense research on NF-κB, its mechanisms in the ischemic brain have not been clearly elucidated. We investigated the temporal profile of NF-κB-related genes using a complementary DNA array method in wild-type mice and human copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had low-level reactive oxygen species (ROS) by scavenging superoxide. Our DNA array showed that IκB kinase (IKK) complex (IKKα, β, and γ) mRNA in the wild-type mice was decreased as early as 1 h after reperfusion, after 30 mins of transient focal cerebral ischemia (tFCI). In contrast, tFCI in the SOD1 Tg mice caused an increase in the IKK complex. The IKK complex protein levels were also drastically decreased at 1 h in the wild-type mice, but did not change in the SOD1 Tg mice throughout the 7 days. Electrophoretic mobility shift assay revealed activation of NF-κB DNA binding after tFCI in the wild-type mice. Nuclear factor-κB activation occurred at the same time, as did the phosphorylation and degradation of the inhibitory protein κBα. However, SOD1 prevented NF-κB activation, and phosphorylation and degradation of IκBα after tFCI. Superoxide production and ubiquitinated protein in the SOD1 Tg mice were also lower than in the wild-type mice after tFCI. These results suggest that ROS are implicated in transient downregulation of IKKα, β, and γ in cerebral ischemia.

Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

2007 ◽  
Vol 67 (4) ◽  
pp. 559-562 ◽  
Author(s):  
K Warstat ◽  
T Pap ◽  
G Klein ◽  
S Gay ◽  
W K Aicher
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Synovial Fibroblasts ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
The Matrix ◽  
Specific Tissue ◽  
Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

scholarly journals DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways

2018 ◽  
Vol 475 (22) ◽  
pp. 3595-3607 ◽  
Author(s):  
Anthony Fullam ◽  
Lili Gu ◽  
Yvette Höhn ◽  
Martina Schröder
Keyword(s):  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Type I Interferons ◽  
Signalling Pathways ◽  
Type I ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Disease States ◽  
Dead Box ◽  
Iκb Kinase

DDX3 is a DEAD-box RNA helicase that we and others have previously implicated in antiviral immune signalling pathways leading to type I interferon (IFN) induction. We previously demonstrated that it directly interacts with the kinase IKKε (IκB kinase ε), enhances it activation, and then facilitates phosphorylation of the transcription factor IRF3 by IKKε. However, the TLR7/9 (Toll-like receptor 7/9)-mediated pathway, one of the most physiologically relevant IFN induction pathways, proceeds independently of IKKε or the related kinase TBK1 (TANK-binding kinase 1). This pathway induces type I IFN production via the kinases NIK (NF-κB-inducing kinase) and IKKα and is activated when plasmacytoid dendritic cells sense viral nucleic acids. In the present study, we demonstrate that DDX3 also directly interacts with IKKα and enhances its autophosphorylation and -activation. Modulation of DDX3 expression consequently affected NIK/IKKα-mediated IRF7 phosphorylation and induction of type I interferons. In addition, alternative NF-κB (nuclear factor-κB) activation, another pathway regulated by NIK and IKKα, was also down-regulated in DDX3 knockdown cells. This substantially broadens the effects of DDX3 in innate immune signalling to pathways beyond TBK1/IKKε and IFN induction. Dysregulation of these pathways is involved in disease states, and thus, our research might implicate DDX3 as a potential target for their therapeutic manipulation.

scholarly journals Bradykinin Induces Interleukin-6 Expression in Astrocytes Through Activation of Nuclear Factor-κB

2002 ◽  
Vol 73 (4) ◽  
pp. 1461-1466 ◽  
Author(s):  
Markus Schwaninger ◽  
Svea Sallmann ◽  
Nicole Petersen ◽  
Armin Schneider ◽  
Simone Prinz ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Nuclear Factor Κb ◽  
Nuclear Factor
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