NF-κB signaling pathway Dotaz Zobrazit nápovědu
BACKGROUND AND HYPOTHESIS: Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of IL-6, TRAF-1, and NAF-1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by PAS-, Masson trichrome-, and Sirius-Red-staining as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine-ratio are markedly increased in NF-κB activated and inactivated mice compared to controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.
- Klíčová slova
- chronic kidney disease, hypertension, inflammation, nf-κb mutant mice, nf-κb signaling,
- Publikační typ
- časopisecké články MeSH
Multiple myeloma, which ranks as the second most common hematological malignancy, is known for its great genetic heterogeneity. One pathway, however, stands out in this diverse group. NF-κB pathway is one of the most important pathways in multiple myeloma not only for its role in pathogenesis, but also for its importance in various treatment strategies. Mutations in several major components of the NF-κB pathway and its regulators are present in at least 17% of primary multiple myeloma tumors and 42% of multiple myeloma cell lines. The NF-κB pathway regulates numerous genes, which influence development and pathogenesis of multiple myeloma. This significance of NF-κB for myeloma cells, however, is used against them, as current treatment strategies often use NF-κB as their primary or secondary target.
- Klíčová slova
- Bone marrow, Multiple myeloma, NF-κB, Proteasome inhibitor, Therapy,
- MeSH
- aktivace enzymů MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- cílená molekulární terapie MeSH
- kostní dřeň účinky léků metabolismus patologie MeSH
- lidé MeSH
- management nemoci MeSH
- mnohočetný myelom diagnóza etiologie metabolismus terapie MeSH
- NF-kappa B antagonisté a inhibitory metabolismus MeSH
- signální transdukce * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- antitumorózní látky MeSH
- NF-kappa B MeSH
The transcription factor c-Myb can be involved in the activation of many genes with protumorigenic function; however, its role in breast cancer (BC) development is still under discussion. c-Myb is considered as a tumor-promoting factor in the early phases of BC, on the other hand, its expression in BC patients relates to a good prognosis. Previously, we have shown that c-Myb controls the capacity of BC cells to form spontaneous lung metastasis. Reduced seeding of BC cells to the lungs is linked to high expression of c-Myb and a decline in expression of a specific set of inflammatory genes. Here, we unraveled a c-Myb-IL1α-NF-κB signaling axis that takes place in tumor cells. We report that an overexpression of c-Myb interfered with the activity of NF-κB in several BC cell lines. We identified IL1α to be essential for this interference since it was abrogated in the IL1α-deficient cells. Overexpression of IL1α, as well as addition of recombinant IL1α protein, activated NF-κB signaling and restored expression of the inflammatory signature genes suppressed by c-Myb. The endogenous levels of c-Myb negatively correlated with IL1α on both transcriptional and protein levels across BC cell lines. We concluded that inhibition of IL1α expression by c-Myb reduces NF-κB activity and disconnects the inflammatory circuit, a potentially targetable mechanism to mimic the antimetastatic effect of c-Myb with therapeutic perspective.
- Klíčová slova
- Breast cancer, IL1α, Inflammation, NF-κB, Transactivation, c-Myb,
- MeSH
- epitelo-mezenchymální tranzice MeSH
- interleukin-1alfa metabolismus MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- nádorové biomarkery metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory prsu etiologie metabolismus patologie MeSH
- NF-kappa B metabolismus MeSH
- protoonkogenní proteiny c-myb metabolismus MeSH
- sekvence aminokyselin MeSH
- signální transdukce * MeSH
- stres endoplazmatického retikula MeSH
- zánět genetika metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- IL1A protein, human MeSH Prohlížeč
- interleukin-1alfa MeSH
- mediátory zánětu MeSH
- MYB protein, human MeSH Prohlížeč
- nádorové biomarkery MeSH
- NF-kappa B MeSH
- protoonkogenní proteiny c-myb MeSH
BACKGROUND: Traumatic spinal cord injury (SCI) triggers a chain of events that is accompanied by an inflammatory reaction leading to necrotic cell death at the core of the injury site, which is restricted by astrogliosis and apoptotic cell death in the surrounding areas. Activation of nuclear factor-κB (NF-κB) signaling pathway has been shown to be associated with inflammatory response induced by SCI. Here, we elucidate the pattern of activation of NF-κB in the pathology of SCI in rats and investigate the effect of transplantation of spinal neural precursors (SPC-01) on its activity and related astrogliosis. METHODS: Using a rat compression model of SCI, we transplanted SPC-01 cells or injected saline into the lesion 7 days after SCI induction. Paraffin-embedded sections were used to assess p65 NF-κB nuclear translocation at days 1, 3, 7, 10, 14, and 28 and to determine levels of glial scaring, white and gray matter preservation, and cavity size at day 28 after SCI. Additionally, levels of p65 phosphorylated at Serine536 were determined 10, 14, and 28 days after SCI as well as levels of locally secreted TNF-α. RESULTS: We determined a bimodal activation pattern of canonical p65 NF-κB signaling pathway in the pathology of SCI with peaks at 3 and 28 days after injury induction. Transplantation of SCI-01 cells resulted in significant downregulation of TNF-α production at 10 and 14 days after SCI and in strong inhibition of p65 NF-κB activity at 28 days after SCI, mainly in the gray matter. Moreover, reduced formation of glial scar was found in SPC-01-transplanted rats along with enhanced gray matter preservation and reduced cavity size. CONCLUSIONS: The results of this study demonstrate strong immunomodulatory properties of SPC-01 cells based on inhibition of a major signaling pathway. Canonical NF-κB pathway activation underlines much of the immune response after SCI including cytokine, chemokine, and apoptosis-related factor production as well as immune cell activation and infiltration. Reduced inflammation may have led to observed tissue sparing. Additionally, such immune response modulation could have impacted astrocyte activation resulting in a reduced glial scar.
- Klíčová slova
- Inflammation, NF-κB, Spinal cord injury, Stem cells transplantation, TNF-α, p65,
- MeSH
- časové faktory MeSH
- cytokiny metabolismus MeSH
- gliový fibrilární kyselý protein metabolismus MeSH
- glióza chirurgie MeSH
- kmenové buňky fyziologie MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- poranění míchy komplikace MeSH
- potkani Wistar MeSH
- signální transdukce fyziologie MeSH
- transformované buněčné linie MeSH
- transkripční faktor RelA metabolismus MeSH
- transplantace kmenových buněk metody MeSH
- zánět etiologie chirurgie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cytokiny MeSH
- gliový fibrilární kyselý protein MeSH
- Rela protein, rat MeSH Prohlížeč
- transkripční faktor RelA MeSH
Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.
- MeSH
- buněčné linie MeSH
- cyklooxygenasy metabolismus MeSH
- inhibitory enzymů farmakologie MeSH
- lidé MeSH
- lipoxygenasy metabolismus MeSH
- NF-kappa B antagonisté a inhibitory MeSH
- prenylace * MeSH
- signální transdukce účinky léků MeSH
- stilbeny farmakologie MeSH
- transkripční faktor AP-1 antagonisté a inhibitory MeSH
- zánět prevence a kontrola MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cyklooxygenasy MeSH
- inhibitory enzymů MeSH
- lipoxygenasy MeSH
- NF-kappa B MeSH
- stilbeny MeSH
- transkripční faktor AP-1 MeSH
UNLABELLED: As the main component of the Gram-negative bacterial cell wall, lipopolysaccharide (LPS) is well documented as an inducer of inflammation in bovine mammary cells. Lycium barbarum (goji) polysaccharides (LBP) have been used in nonruminants as prebiotics to improve growth performance, immune ability, and antioxidant capacity. We aimed to investigate the underlying effects of LBPs on proinflammatory responses in LPS-stimulated primary bovine mammary epithelial cells (bMECs). Cells were isolated from mammary tissue of three lactating Holstein cows without clinical disease (30.26 ± 3.1 kg/d of milk yield; 175 ± 6 DIM). For the pre-experimental treatment, bMECs were precultured with serum-free medium for 12 h. Treatments were as follows: pretreatment with culture medium devoid of LPS or LBP for 30 h (CON); CON for 24 h followed by challenge with 2 μg/mL LPS for 6 h (LPS); pretreatment with 100 or 300 μg/mL LBP for 24 h followed by LPS challenge (2 μg/mL) for 6 h (LBP(100)+LPS; LBP(300)+LPS). To further determine if the effect of LBP on immuneregulation is peroxisome proliferator-activated receptor-γ (PPARγ) activation dependent, an inhibitor of PPARγ, GW9662, at a concentration of 1 μM was used. Cells treated with LBP at 100, 300, and 500 μg/mL had upregulated protein abundance of PPARγ, while PGC1α had a higher expression only at 300 μg/mL of LBP treatment. Compared with CON, cells pretreated with LBP at 100 and 300 μg/mL had greater protein abundance of SCD1 and SREBP1. 5-Ethynyl-2'-deoxyuridine (EdU) staining and cell wound healing assays showed that the negative effect of LPS alone on cell proliferation was reversed by pretreatment with LBP at both 100 and 300 μg/mL. Upregulation of gene and protein abundance of proinflammatory factors and cytokines (COX-2, NLRP3, TNF-α, IL-1β, and IL-6) induced by LPS stimulation were alleviated by LBP pretreatment at 300 μg/mL (more than 2-fold decrease). Compared with LPS challenge alone, phosphorylation of proteins involved in NF-κB (IκBα and p65) and MAPK (p38, JNK, and ERK) pathways was downregulated following LBP treatment. Additionally, inhibition of PPARγ by GW9662 weakened the protective effect of LBP on LPS-induced protein abundance of phosphorylated p65, COX-2, IL-1β, and TNF-α. These results indicated that the protective effect of LBP on LPS-induced bMECs inflammatory responses is PPARγ activation-dependent. As such, this knowledge might help design strategies for intervening against the detrimental effects of bovine mastitis. INTERPRETIVE SUMMARY: Current research examined Lycium barbarum polysaccharides (LBP) for combating LPS-induced inflammatory responses in primary bovine mammary epithelial cells. We uncovered a preventive role of LBP in reducing detrimental effects induced by LPS including inhibition of NF-κB and MAPK along with peroxisome proliferator-activated receptor-γ (PPARγ) activation. The decrease in cell proliferation due to LPS was curtailed by pretreatment with LBP. Moreover, the effect of LBP on regulation of inflammatory responses in bovine mammary epithelial cell was PPARγ dependent. Collectively, data suggest that LBP reverses LPS-induced inflammatory response via MAPK/NF-κB signaling in a PPARγ-activation-dependent manner. Thus, the study provides new insights into therapeutic strategies for combating mastitis using LBP and highlighted the link between PPARγ and regulation of mammary cell inflammation.
- Klíčová slova
- Lycium barbarum polysaccharides, NF-κB signaling pathway, PPARγ, bovine mammary cells, inflammatory responses,
- MeSH
- epitelové buňky MeSH
- kustovnice * MeSH
- laktace MeSH
- lipopolysacharidy MeSH
- mléčné žlázy zvířat MeSH
- nemoci skotu * MeSH
- NF-kappa B MeSH
- PPAR gama genetika MeSH
- skot MeSH
- zánět chemicky indukované farmakoterapie veterinární MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- lipopolysacharidy MeSH
- NF-kappa B MeSH
- PPAR gama MeSH
NF-κB pathway is involved in inflammation; however, recent data shows its role also in cancer development and progression, including metastasis. To understand the role of NF-κB interactome dynamics in cancer, we study the complexity of breast cancer interactome in luminal A breast cancer model and its rearrangement associated with NF-κB modulation. Liquid chromatography-mass spectrometry measurement of 160 size-exclusion chromatography fractions identifies 5460 protein groups. Seven thousand five hundred sixty eight interactions among these proteins have been reconstructed by PrInCE algorithm, of which 2564 have been validated in independent datasets. NF-κB modulation leads to rearrangement of protein complexes involved in NF-κB signaling and immune response, cell cycle regulation, and DNA replication. Central NF-κB transcription regulator RELA co-elutes with interactors of NF-κB activator PRMT5, and these complexes are confirmed by AlphaPulldown prediction. A complementary immunoprecipitation experiment recapitulates RELA interactions with other NF-κB factors, associating NF-κB inhibition with lower binding of NF-κB activators to RELA. This study describes a network of pro-tumorigenic protein interactions and their rearrangement upon NF-κB inhibition with potential therapeutic implications in tumors with high NF-κB activity.
- Klíčová slova
- AlphaPullDown, NF-κB, RELA, breast cancer, interaction, protein complexes, protein correlation profiling, proteomics,
- MeSH
- karcinogeneze metabolismus MeSH
- lidé MeSH
- mapování interakce mezi proteiny MeSH
- mapy interakcí proteinů * MeSH
- nádorové buněčné linie MeSH
- nádory prsu * metabolismus patologie MeSH
- NF-kappa B * metabolismus MeSH
- proteinarginin-N-methyltransferasy metabolismus MeSH
- signální transdukce MeSH
- transkripční faktor RelA * metabolismus MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- NF-kappa B * MeSH
- proteinarginin-N-methyltransferasy MeSH
- RELA protein, human MeSH Prohlížeč
- transkripční faktor RelA * MeSH
Oxidative stress is closely linked to the toxic responses of various cell types in normal and pathophysiological conditions. Deoxynivalenol (DON), an inducer of stress responses in the ribosome and the endoplasmic reticulum (ER), causes mitochondrial dysfunction and mitochondria-dependent apoptosis through oxidative stress in humans and animals. The NF-κB pathway, which is closely linked to oxidative stress, is hypothesized to be a critical signaling pathway for DON-induced toxicity and is a potential target for intervention. The present study was conducted to explore the protective effects of pyrrolidine dithiocarbamate (PDTC) from the toxic effects of DON in rat anterior pituitary GH3 cells. Our results showed that DON activated the NF-κB transcription factors and induced cellular oxidative stress, mitochondrial dysfunction, and apoptosis. Morphological studies using transmission electron microscopy (TEM) and cell apoptosis analyses suggested that PDTC prevented DON-induced mitochondrial dysfunction and apoptosis, probably by preventing the DON-induced translocation of NF-κB p65 into the nucleus, and by inhibiting DON-induced iNOS expression. This led to the blocking of the NF-κB pathway and inhibition of iNOS activity.
- MeSH
- antioxidancia MeSH
- apoptóza MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- NF-kappa B metabolismus MeSH
- oxidační stres MeSH
- pyrrolidiny farmakologie terapeutické užití MeSH
- signální transdukce MeSH
- thiokarbamáty farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antioxidancia MeSH
- NF-kappa B MeSH
- pyrrolidine dithiocarbamic acid MeSH Prohlížeč
- pyrrolidiny MeSH
- thiokarbamáty MeSH
Nuclear factor kappa B (NF-κB) signaling plays critical roles in many physiological and pathological processes, including regulating organogenesis. Down-regulation of NF-κB signaling during development results in hypohidrotic ectodermal dysplasia. The roles of NF-κB signaling in tooth development, however, are not fully understood. We examined mice overexpressing IKKβ, an essential component of the NF-κB pathway, under keratin 5 promoter (K5-Ikkβ). K5-Ikkβ mice showed supernumerary incisors whose formation was accompanied by up-regulation of canonical Wnt signaling. Apoptosis that is normally observed in wild-type incisor epithelium was reduced in K5-Ikkβ mice. The supernumerary incisors in K5-Ikkβ mice were found to phenocopy extra incisors in mice with mutations of Wnt inhibitor, Wise. Excess NF-κB activity thus induces an ectopic odontogenesis program that is usually suppressed under physiological conditions.
- Klíčová slova
- Ikkβ, Wnt signaling, cervical loop, enamel, tooth development, wise,
- MeSH
- adaptorové proteiny signální transdukční MeSH
- ameloblasty cytologie MeSH
- amelogenin analýza MeSH
- apoptóza fyziologie MeSH
- epitel embryologie MeSH
- fenotyp MeSH
- keratin-15 genetika MeSH
- kinasa I-kappa B fyziologie MeSH
- kostní morfogenetické proteiny genetika MeSH
- mikroradiografie metody MeSH
- mutace genetika MeSH
- mutantní kmeny myší MeSH
- myši MeSH
- NF-kappa B fyziologie MeSH
- odontogeneze fyziologie MeSH
- Patched receptory MeSH
- promotorové oblasti (genetika) genetika MeSH
- proteiny hedgehog fyziologie MeSH
- receptory buněčného povrchu fyziologie MeSH
- rentgenová mikrotomografie metody MeSH
- řezáky abnormality embryologie MeSH
- signální dráha Wnt genetika fyziologie MeSH
- zobrazování trojrozměrné metody MeSH
- zubní sklovina cytologie MeSH
- zubní zárodek abnormality embryologie MeSH
- zuby přespočetné etiologie genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- amelogenin MeSH
- Chuk protein, mouse MeSH Prohlížeč
- keratin-15 MeSH
- kinasa I-kappa B MeSH
- kostní morfogenetické proteiny MeSH
- Krt15 protein, mouse MeSH Prohlížeč
- NF-kappa B MeSH
- Patched receptory MeSH
- proteiny hedgehog MeSH
- receptory buněčného povrchu MeSH
- Shh protein, mouse MeSH Prohlížeč
- Sostdc1 protein, mouse MeSH Prohlížeč
AIMS: Endoglin is a transmembrane glycoprotein, that plays an important role in regulating endothelium. Proteolytic cleavage of membrane endoglin releases soluble endoglin (sEng), whose increased plasma levels have been detected in diseases related to the cardiovascular system. It was proposed that sEng might damage vascular endothelium, but detailed information about the potential mechanisms involved is not available. Thus, we hypothesized that sEng contributes to endothelial dysfunction, leading to a pro-inflammatory phenotype by a possible modulation of the TGF-β and/or inflammatory pathways. MAIN METHODS: Human umbilical vein endothelial cells (HUVECs) and Human embryonic kidney cell line (HEK293T) were treated with different sEng concentration and time in order to reveal possible effect on biomarkers of inflammation and TGF-β signaling. IL6 and NFκB reporter luciferase assays, quantitative real-time PCR analysis, Western blot analysis and immunofluorescence flow cytometry were used. KEY FINDINGS: sEng treatment results in activation of NF-κB/IL-6 expression, increased expression of membrane endoglin and reduced expression of Id-1. On the other hand, no significant effects on other markers of endothelial dysfunction and inflammation, including eNOS, peNOSS1177, VCAM-1, COX-1, COX-2 and ICAM-1 were detected. SIGNIFICANCE: As a conclusion, sEng treatment resulted in an activation of NF-κB, IL-6, suggesting activation of pro-inflammatory phenotype in endothelial cells. The precise mechanism of this activation and its consequence remains to be elucidated. A combined treatment of sEng with other cardiovascular risk factors will be necessary in order to reveal whether sEng is not only a biomarker of cardiovascular diseases, but also a protagonist of endothelial dysfunction.
- Klíčová slova
- Endothelial cells, IL-6, Inflammation, NF-κB, Soluble endoglin,
- MeSH
- endoglin biosyntéza MeSH
- endoteliální buňky pupečníkové žíly (lidské) metabolismus MeSH
- HEK293 buňky MeSH
- inhibitor diferenciace 1 biosyntéza MeSH
- interleukin-6 biosyntéza MeSH
- lidé MeSH
- NF-kappa B biosyntéza MeSH
- regulace genové exprese * MeSH
- rozpustnost MeSH
- signální transdukce * MeSH
- zánět chemicky indukované metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- endoglin MeSH
- ENG protein, human MeSH Prohlížeč
- ID1 protein, human MeSH Prohlížeč
- IL6 protein, human MeSH Prohlížeč
- inhibitor diferenciace 1 MeSH
- interleukin-6 MeSH
- NF-kappa B MeSH