Dynein Light Chain LC8 Alleviates Nonalcoholic Steatohepatitis By Regulating Nuclear Factor κB Through Interference With IκBα Phosphorylation

2021 ◽  
Author(s):  
Gong-Rak Lee ◽  
Hye In Lee ◽  
Narae Kim ◽  
Jiae Lee ◽  
Minjeong Kwon ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Light Chain ◽  
Nonalcoholic Steatohepatitis ◽  
Nuclear Translocation ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Dynein Light Chain ◽  
Hepatic Expression ◽  
Iκbα Phosphorylation

Abstract Nonalcoholic steatohepatitis (NASH) is a liver disease characterized by fat accumulation and chronic inflammation in the liver. Although dynein light chain of 8 kDa (LC8) was identified previously as an inhibitor of nuclear factor kappa B (NF-κB), a key regulator of inflammation, its role in NASH remains unknown. In this study, we investigated whether LC8 can alleviate NASH using a mouse model of methionine and choline-deficient (MCD) diet–induced NASH and examined the underlying mechanism. LC8 transgenic (Tg) mice showed lower hepatic steatosis and less progression of NASH, including inflammation, oxidative stress, and hepatic fibrosis, compared to wild-type (WT) mice after consuming an MCD diet. The hepatic expression of lipogenic genes was lower, while that of lipolytic and mitochondrial genes was greater in LC8 Tg mice than WT mice, which might be associated with resistance of LC8 Tg mice to hepatic steatosis. Consumption of an MCD diet enhanced IκBα phosphorylation and subsequent p65 liberation from IκBα and nuclear translocation, resulting in induction of NF-κB targets, including pro-inflammatory cytokines and chemokines. However, these effects of MCD diet were reduced by LC8 overexpression. Taken together, these results suggest that LC8 alleviates MCD diet–induced NASH by inhibiting NF-κB through binding to IκBα to interfere with IκBα phosphorylation.

Abstract 501: Nuclear Factor-κB Is Involved in Platelet CD40 Signaling and Activation

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ahmed Hachem ◽  
Daniel Yacoub ◽  
Younes Zaid ◽  
Walid Mourad ◽  
Yahye Merhi
Keyword(s):  
P38 Mapk ◽  
Platelet Activation ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Factor ◽  
Iκb Kinase ◽  
Iκbα Phosphorylation

Introduction and hypothesis: CD40 ligand (CD40L) is a thrombo-inflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40L (sCD40L), which has been shown to influence platelet activation. We have previously shown that upon ligation, CD40 potentiates platelet activation and aggregation via p38 mitogen activated protein kinase (MAPK) and Rac1 signaling. In B lymphocytes, CD40 induces activation and nuclear translocation of nuclear factor kappa B (NF-κB), which is dependent on the phosphorylation and dissociation of the inhibitor of kappa B α (IκBα). Given that platelets contain NF-κB, we hypothesized that it may be involved in platelet CD40 signaling. Methods and results: In human platelets, sCD40L induced association of tumor necrosis factor receptor associated factor 2 to CD40, and a time-dependant phosphorylation of IκBα, which is indicative of NF-κB activation. Activation of NF-κB in platelets treated with sCD40L was abolished by CD40L blockade. Pretreatment of platelets with the IκBα inhibitor, BAY 11-7082, reversed IκBα phosphorylation induced by sCD40L, without affecting p38 MAPK activation. On the other hand, pretreatment of platelets with the p38 MAPK phosphorylation inhibitor, SB203580, had no effect on IκBα phosphorylation, indicating a divergence in the signaling pathway originating from CD40 upon its ligation. Finally, inhibition of IκBα phosphorylation by either BAY 11-7082 or the IκB kinase inhibitor VII reversed sCD40L induced platelet activation, as measured by P-selectin expression, and the potentiation of platelet aggregation induced by a priming dose of collagen. Conclusion: This study demonstrates the implication of NF-κB in platelet signaling downstream of CD40, where it plays a role in platelet activation and aggregation upon sCD40L stimulation.

scholarly journals Activation of Nuclear Factor κb and bcl-x Survival Gene Expression by Nerve Growth Factor Requires Tyrosine Phosphorylation of IκBα

2001 ◽  
Vol 152 (4) ◽  
pp. 753-764 ◽  
Author(s):  
Nguyen Truc Bui ◽  
Antonia Livolsi ◽  
Jean-Francois Peyron ◽  
Jochen H.M. Prehn
Keyword(s):  
Gene Expression ◽  
Tyrosine Phosphorylation ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Nuclear Factor ◽  
Human Neuroblastoma ◽  
Tnf Α

NGF has been shown to support neuron survival by activating the transcription factor nuclear factor-κB (NFκB). We investigated the effect of NGF on the expression of Bcl-xL, an anti–apoptotic Bcl-2 family protein. Treatment of rat pheochromocytoma PC12 cells, human neuroblastoma SH-SY5Y cells, or primary rat hippocampal neurons with NGF (0.1–10 ng/ml) increased the expression of bcl-xL mRNA and protein. Reporter gene analysis revealed a significant increase in NFκB activity after treatment with NGF that was associated with increased nuclear translocation of the active NFκB p65 subunit. NGF-induced NFκB activity and Bcl-xL expression were inhibited in cells overexpressing the NFκB inhibitor, IκBα. Unlike tumor necrosis factor-α (TNF-α), however, NGF-induced NFκB activation occurred without significant degradation of IκBs determined by Western blot analysis and time-lapse imaging of neurons expressing green fluorescent protein–tagged IκBα. Moreover, in contrast to TNF-α, NGF failed to phosphorylate IκBα at serine residue 32, but instead caused significant tyrosine phosphorylation. Overexpression of a Y42F mutant of IκBα potently suppressed NFG-, but not TNF-α–induced NFκB activation. Conversely, overexpression of a dominant negative mutant of TNF receptor-associated factor-6 blocked TNF-α–, but not NGF-induced NFκB activation. We conclude that NGF and TNF-α induce different signaling pathways in neurons to activate NFκB and bcl-x gene expression.

scholarly journals Cell-specific Activation of Nuclear Factor-κB by the ParasiteTrypanosoma cruziPromotes Resistance to Intracellular Infection

2000 ◽  
Vol 11 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Belinda S. Hall ◽  
Winnie Tam ◽  
Ranjan Sen ◽  
Miercio E. A. Pereira
Keyword(s):  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Microbial Pathogens ◽  
Tissue Tropism ◽  
Nuclear Factor ◽  
Infection Level ◽  
Direct Role ◽  
Intracellular Infection

The transcription factor nuclear factor-κB (NF-κB) is central to the innate and acquired immune response to microbial pathogens, coordinating cellular responses to the presence of infection. Here we demonstrate a direct role for NF-κB activation in controlling intracellular infection in nonimmune cells. Trypanosoma cruzi is an intracellular parasite of mammalian cells with a marked preference for infection of myocytes. The molecular basis for this tissue tropism is unknown. Trypomastigotes, the infectious stage of T. cruzi, activate nuclear translocation and DNA binding of NF-κB p65 subunit and NF-κB-dependent gene expression in epithelial cells, endothelial cells, and fibroblasts. Inactivation of epithelial cell NF-κB signaling by inducible expression of the inhibitory mutant IκBaM significantly enhances parasite invasion.T. cruzi do not activate NF-κB in cells derived from skeletal, smooth, or cardiac muscle, despite the ability of these cells to respond to tumor necrosis factor-α with NF-κB activation. The in vitro infection level in these muscle-derived cells is more than double that seen in the other cell types tested. Therefore, the ability of T. cruzi to activate NF-κB correlates inversely with susceptibility to infection, suggesting that NF-κB activation is a determinant of the intracellular survival and tissue tropism ofT. cruzi.

Acetaminophen down-regulates interleukin-1β-induced nuclear factor-κB nuclear translocation in a human astrocytic cell line

2003 ◽  
Vol 353 (2) ◽  
pp. 79-82 ◽  
Author(s):  
Francesca Mancini ◽  
Carla Landolfi ◽  
Marta Muzio ◽  
Luciano Aquilini ◽  
Lucia Soldo ◽  
...  
Keyword(s):  
Cell Line ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Interleukin 1Β ◽  
Nuclear Factor

Resveratrol promotes recovery of immune function of immunosuppressive mice by activating JNK/NF-κB pathway in splenic lymphocytes

2017 ◽  
Vol 95 (6) ◽  
pp. 763-767 ◽  
Author(s):  
Xin Lai ◽  
Mei Cao ◽  
Xu Song ◽  
Renyong Jia ◽  
Yuanfeng Zou ◽  
...  
Keyword(s):  
Natural Compound ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Spleen Lymphocyte ◽  
Splenic Lymphocytes ◽  
Jnk Pathway ◽  
Immunologic Function ◽  
Iκb Kinase ◽  
Regulatory Effects

Resveratrol, a natural compound found in over 70 plants, is known to possess immunoregulatory effects and anti-inflammatory activity. It has been shown that resveratrol has regulatory effects on different signaling pathways in different diseases. However, few reports have evaluated the effects of resveratrol on reinforcing immunity recovery via activating nuclear factor-κB (NF-κB) pathway and Jun N-terminal kinases (JNK) pathway. The present study aimed to assess immune-enhancing activity and underlying mechanism of resveratrol in immunosuppressive mice. Previously, we reported that resveratrol could promote mouse spleen lymphocyte functions to recover the immune system effectively. In the present study, we show that resveratrol could upregulate the expressions of NF-κB, IκB kinase, JNK, and c-jun in splenic lymphocytes of immunosuppressive mice. Taken together, our results indicate that resveratrol could promote recovery of immunologic function in immunosuppressive mice by activating JNK/NF-κB pathway.

scholarly journals Tumor protein D52 (isoform 3) contributes to prostate cancer cell growth via targeting nuclear factor-κB transactivation in LNCaP cells

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769838 ◽  
Author(s):  
Chandrashekhar Dasari ◽  
Dattu Prasad Yaghnam ◽  
Reinhard Walther ◽  
Ramesh Ummanni
Keyword(s):  
Prostate Cancer ◽  
Cell Adhesion ◽  
Cancer Progression ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Nuclear Factor ◽  
Prostate Cancer Progression ◽  
Lncap Cells ◽  
Cancer Cell Growth

Our previous study showed that TPD52 overexpression could increase migration and proliferation of LNCaP cells contributing to the development of prostate cancer. However, mechanism of TPD52 in prostate cancer initiation and progression remains elusive. In this study, we investigated the possible underlying mechanism of TPD52 in prostate cancer progression. In LNCaP cells, TPD52 expression was altered by transfecting with either EGFP-TPD52 or specific short hairpin RNA. Overexpression of TPD52 protected LNCaP cells from apoptosis through elevated anti-apoptotic proteins XIAP, Bcl-2, and Cyclin D1, whereas Bax was downregulated. Mechanistically, we found that TPD52 confers transactivation of nuclear factor-κB, thereby enhancing its target gene expression in LNCaP cells. TPD52 promotes LNCaP cell invasion probably via increased matrix metalloproteinase 9 expression and its activity while tissue inhibitor of metalloproteinase expression is significantly downregulated. Notably, TPD52 might be involved in cell adhesion, promoting tumor metastasis by inducing loss of E-cadherin, expression of vimentin and vascular cell adhesion molecule, and additionally activation of focal adhesion kinase. Furthermore, TPD52 directly interacts with nuclear factor-κB p65 (RelA) and promotes accumulation of phosphorylated nuclear factor-κB (p65)S536 that is directly linked with nuclear factor-κB transactivation. Indeed, depletion of TPD52 or inhibition of nuclear factor-κB in TPD52-positive cells inhibited secretion of tumor-related cytokines and contributes to the activation of STAT3, nuclear factor-κB, and Akt. Interestingly, in TPD52 overexpressing LNCaP cells, nuclear factor-κB inhibition prevented the autocrine/paracrine activation of STAT3. TPD52 activates STAT3 through ascertaining a cross talk between the nuclear factor-κB and the STAT3 signaling systems. Collectively, these results reveal mechanism by which TPD52 is associated with prostate cancer progression and highlight the approach for therapeutic targeting of TPD52 in prostate cancer.

scholarly journals Mild Hypothermia Inhibits Nuclear Factor-κB Translocation in Experimental Stroke

2003 ◽  
Vol 23 (5) ◽  
pp. 589-598 ◽  
Author(s):  
Hyung Soo Han ◽  
Murat Karabiyikoglu ◽  
Stephen Kelly ◽  
Raymond A. Sobel ◽  
Midori A. Yenari
Keyword(s):  
Target Genes ◽  
Nuclear Translocation ◽  
Mild Hypothermia ◽  
Brain Temperature ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Cerebral Injury ◽  
Experimental Stroke ◽  
Nuclear Factor ◽  
Iκb Kinase

Nuclear factor-κB (NFκB) is a transcription factor that is activated after cerebral ischemia. NFκB activation leads to the expression of many inflammatory genes involved in the pathogenesis of stroke. The authors previously showed that mild hypothermia is protective even when cooling begins 2 h after stroke onset. In the present study, they examined the influence of hypothermia on NFκB activation. Rats underwent 2 h of transient middle cerebral artery occlusion. Brains were cooled to 33°C immediately after or 2 h after occlusion, and maintained for 2 h. After normothermic ischemia (brain temperature at 38°C), NFκB cytoplasmic expression, nuclear translocation, and binding activity were observed as early as 2 h in the ischemic hemisphere and persisted at 24 h. Hypothermia decreased NFκB translocation and binding activity but did not alter overall expression. Hypothermia also affected the levels of NFκB regulatory proteins by suppressing phosphorylation of NFκB's inhibitory protein (IκB-α) and IκB kinase (IKK-γ) and decreasing IKK activity, but did not alter overall IKK levels. Hypothermia suppressed the expression of two NFκB target genes: inducible nitric oxide synthase and TNF-α. These data suggest that the protective effect of hypothermia on cerebral injury is, in part, related to NFκB inhibition due to decreased activity of IKK.

Nuclear Factor-κB–Dependent Induction of Interleukin-8 Gene Expression by Tumor Necrosis Factor : Evidence for an Antioxidant Sensitive Activating Pathway Distinct From Nuclear Translocation

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1878-1889 ◽  
Author(s):  
Spiros Vlahopoulos ◽  
Istvan Boldogh ◽  
Antonella Casola ◽  
Allan R. Brasier
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis Factor ◽  
Transcriptional Activation ◽  
Tumor Necrosis ◽  
Nuclear Translocation ◽  
Gene Transfection ◽  
Nuclear Factor Κb ◽  
Interleukin 8 ◽  
Nuclear Factor ◽  
Necrosis Factor

Tumor necrosis factor  (TNF) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNF-inducible reactive oxygen species (ROS) in IL-8 expression by “monocyte-like” U937 histiocytic lymphoma cells. TNF is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNF requires the presence of an inducible nuclear factor-κB (NF-κB) (Rel A) binding site in the IL-8 promoter. TNF treatment induces a rapid translocation of the 65 kD transcriptional activator NF-κB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNF with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-κB–dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-κB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNF induces a delayed ROS-dependent signalling pathway that is required for NF-κB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNF signalling.

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