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Nuclear Factor Kappa B (nuclear + factor_kappa_b)
Terms modified by Nuclear Factor Kappa B Selected AbstractsPlatelet-activating factor-induced NF-,B activation and IL-8 production in intestinal epithelial cells are Bcl10-dependentINFLAMMATORY BOWEL DISEASES, Issue 4 2010Alip Borthakur PhD Abstract Background: Platelet-activating factor (PAF), a potent proinflammatory phospholipid mediator, has been implicated in inducing intestinal inflammation in diseases such as inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). However, its mechanisms of inducing inflammatory responses are not fully understood. Therefore, studies were designed to explore the mechanisms of PAF-induced inflammatory cascade in intestinal epithelial cells. Methods: Nuclear factor kappa B (NF-,B) activation was measured by luciferase assay and enzyme-linked immunosorbent assay (ELISA), and interleukin 8 (IL-8) production was determined by ELISA. B-cell lymphoma 10 (Bcl10), caspase recruitment domain-containing membrane-associated guanylate kinase protein 3 (CARMA3), and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) mRNA and protein levels were assessed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. siRNA silencing of Bcl10 was used to examine its role in PAF-induced NF-,B activation and IL-8 production. The promoter region of the Bcl10 gene was cloned with the PCR method and promoter activity measured by luciferase assay. Results: The adaptor protein Bcl10 appeared to play an important role in the PAF-induced inflammatory pathway in human intestinal epithelial cells. Bcl10 was required for PAF-induced I,B, phosphorylation, NF-,B activation, and IL-8 production in NCM460, a cell line derived from normal human colon, and Caco-2, a transformed human intestinal cell line. PAF also stimulated Bcl10 interactions with CARMA3 and MALT1, and upregulated Bcl10 expression in these cells via transcriptional regulation. Conclusions: These findings highlight a novel PAF-induced inflammatory pathway in intestinal epithelial cells, requiring Bcl10 as a critical mediator and involving CARMA3/Bcl10/MALT1 interactions. The proinflammatory effects of PAF play prominent roles in the pathogenesis of IBD and this pathway may present important targets for intervention in chronic inflammatory diseases of the intestine. (Inflamm Bowel Dis 2009;) [source] , -secretase inhibitors exerts antitumor activity via down-regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cellsORAL DISEASES, Issue 6 2007J Yao Objective:, To investigate the effect of the , -secretase inhibitors (GSIs) on the growth of human tongue carcinoma cells and to provide the molecular mechanism for potential application of GSIs in the treatment of tongue carcinoma. Materials and methods:, Human tongue carcinoma Tca8113 cells were cultured with the GSI L-685 458. Cell growth was determined by the methylthiazole tetrazolium method. Cell cycle and apoptosis were analyzed by flow cytometry and/or confocal microscopy. RT-PCR and Western blot were employed to determine the intracellular expression levels. Nuclear factor kappa B (NF- ,B) activation was examined by electrophoretic mobility shift assay. Results:, L-685,458 dose-dependently inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0,G1 cell cycle arrest and apoptosis. The mRNA and protein levels of Hairy/Enhancer of Split-1, a target of Notch activation, were decreased dose-dependently by L-685,458. Furthermore, L-685,458 down-regulated cyclin D1, B-cell lymphocytic-leukemia proto-oncogene 2 and c-Myc expressions, which are regulated by the transcription factor NF- ,B. Coincident with this observation, L-685,458 induced a dose-dependent reduction of constitutive NF- ,B activation in Tca8113 cells. Conclusions:, The GSI L-685,458 may have a therapeutic value for the treatment of human tongue carcinoma. Moreover, the effects of L-685,458 in tumor inhibition may act partially via the modulation of Notch and NF- ,B. [source] Alteration of NF-,B activity leads to mitochondrial apoptosis after infection with pathological prion proteinCELLULAR MICROBIOLOGY, Issue 9 2007Soizic Bourteele Summary Nuclear factor kappa B (NF-,B) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, proliferation and regulation of apoptosis. In the central nervous system activated NF-,B plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-,B is well characterized, there is poor knowledge on the role of NF-,B in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-,B activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-,B after prion infection of Nfkb1,/,, Nfkb2,/, and Bcl3,/, mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-,B2- and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-,B activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis. [source] The functional role of nuclear factor kappa-,B1 ,94 ins/del ATTG promotor gene polymorphism in Behçet's disease: an exploratory studyCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 5 2008B. Yalcin Summary Behçet's Disease (BD) is a systemic immunoinflammatory disease. The pathogenesis of BD is unknown, although raised levels of several pro-inflammatory cytokines have been reported. Nuclear factor kappa B (NF-,B) is a family of critical transcriptional factors involved in the regulation of a large variety of inflammatory responses and apoptosis. In this study we investigated the ,94 insertion/deletion ATTG promoter polymorphism of the NF-,B1 gene (NFKB1) in 86 patients with BD and 100 healthy controls. The frequency of the ,94ins ATTG (I) allele was 61.6% in patients with BD and 59% in controls and the frequency of the ,94 del ATTG (D) allele was 38.4% in patients with BD and 41% in controls. The frequency of the ,94ins ATTG (I) allele was significantly higher in patients with ocular involvement (P = 0.03). In the genotype study, the overall frequencies of II, ID and DD were 40.7%, 41.9%, and 17.4% in the patient group and 30%, 58% and 12% in the control group (P: 0.08). The II genotype was significantly higher in patients with ocular involvement, genital ulcers or papulopustular lesions. The frequency of the II, ID and DD genotypes showed no marked difference in patients with erythema nodosum, pathergy positivity, arthritis or vascular involvement. No difference was found for gender, positive family history or age at disease onset. This study provides evidence that the ,94ins/del ATTG promoter polymorphism of NFKB1 may have functional consequences in BD, especially in patients with ocular involvement. [source] Cloning and characterization of Dorsal homologues in the hemipteran Rhodnius prolixusINSECT MOLECULAR BIOLOGY, Issue 5 2009R. Ursic-Bedoya Abstract Rhodnius prolixus is an ancient haematophagous hemipteran insect capable of mounting a powerful immune response. This response is transcriptionally regulated in part by transcription factors of the Rel/Nuclear Factor kappa B (Rel/NF-,B) family. We have cloned and characterized three members of this transcription factor family in this insect. Dorsal 1A is primarily expressed in early developmental stages. In contrast, dorsal 1B and 1C, both differentially spliced products of dorsal 1A, are expressed primarily in the adult fat body in response to septic injury, suggesting their exclusive role in immunity. Additionally, we identified putative ,B binding sites in the 5, upstream regions of target genes known to be involved in the innate immune response of insects. [source] NF,B, cytokines, TLR 3 and 7 expression in human end-stage HCV and alcoholic liver diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2010Peter Stärkel Eur J Clin Invest 2010; 40 (7): 575,584 Abstract Background/aims, Conflicting observations exist concerning the role of nuclear factor kappa B (NF,B) in alcoholic liver disease (ALD) in animal models. To date no studies have examined this aspect in human liver tissue. We here assessed cytokines and toll-like receptors (TLRs) expressions in conjunction with NF,B activation in non-active end-stage human ALD compared with normal livers and hepatitis C virus (HCV) related end-stage disease. Methods, mRNA and protein expression were examined by quantitative PCR and Western blotting, DNA-binding by electrophoretic mobility shift assays and NF,B sub-cellular localization by immunofluorescent staining of livers. Results, NF,B mRNA and protein expression as well as strong DNA-binding were preserved in ALD but significantly down-regulated in HCV compared with normal livers. P50 immunofluorescence was found in hepatocytes and bile ducts in ALD and normal livers, whereas a shift was observed in p65 staining from non-parenchymal cells in normal livers to hepatocytes in ALD. NF,B responsive genes mRNA levels IkB, and interleukin 6 were significantly higher in ALD compared with HCV. Tumour necrosis factor alpha (TNF,), TLRs 3 and 7 mRNA were up-regulated in ALD and HCV compared with normal liver with TNF, and TLR7 being the highest in HCV. Strong induction of interferon beta was found in HCV but not in ALD or normal liver tissue. Conclusions, Persistent NF,B activation together with high pro-inflammatory cytokine expression and upregulation of TLR3 and TLR7 is associated with end-stage ALD in humans and could contribute to disease progression even in absence of alcohol intake. [source] Deficient translocation of c-Rel is associated with impaired Th1 cytokine production in T cells from atopic dermatitis patientsEXPERIMENTAL DERMATOLOGY, Issue 1 2005Karsten Dieckhoff Abstract:, Decreased production of T helper type 1 (Th1) cytokines, such as interferon-, (IFN-,) or interleukin-2 (IL-2), is a hallmark of atopic diseases. While accessory signals from antigen-presenting cells may be missing, T cells themselves may be suppressed in their ability to produce substantial amounts of Th1 cytokines. We show, in this study, that T cell receptor (TCR)-activated T cells from atopic dermatitis (AD) patients proliferate less than control T cells and produce lower amounts of IFN-, and IL-2, but comparable amounts of IL-4. Because mice lacking the nuclear factor kappa B (NF-,B) transcription factors , p65 or c-Rel , show reduced Th1, but undisturbed Th2 responses, we investigated the role of c-Rel and p65 for Th1 cytokine production in T cells from healthy and severe AD patients. TCR-activated primary T cells from healthy donors treated with c-Rel antisense oligonucleotides produced lower levels of IL-2 and IFN-, and proliferated less efficiently than the corresponding control T cells. Moreover, transfection of primary T cells with c-Rel or p65 enhanced proliferation and production of IL-2 and IFN-,. Nuclear extracts of activated primary T cells from AD donors bound weakly to NF-,B-specific oligonucleotides, compared to extracts from healthy control T cells. Western blotting studies revealed that nuclear, but not cytosolic, extracts from T cells of AD patients lacked significant amounts of c-Rel and p65. T cell clones derived from AD patients failed to sufficiently translocate c-Rel and p65 into the nucleus following activation. Thus, impaired nuclear translocation of c-Rel and p65 may determine an impaired Th1 cytokine response in AD. [source] The effect of hfq on global gene expression and virulence in Neisseria gonorrhoeaeFEBS JOURNAL, Issue 19 2009Manuela Dietrich Hfq is an RNA chaperone that functions as a pleiotropic regulator for RNA metabolism in bacteria. In several pathogenic bacteria, Hfq contributes indirectly to virulence by binding to riboregulators that modulate the stability or translation efficiency of RNA transcripts. To characterize the role of Hfq in the pathogenicity of Neisseria gonorrhoeae, we generated an N. gonorrhoeae hfq mutant. Infectivity and global changes in gene expression caused by the hfq mutation in N. gonorrhoeae strain MS11 were analyzed. Transcriptional analysis using a custom-made N. gonorrhoeae microarray revealed that 369 ORFs were differentially regulated in the hfq mutant, MS11hfq, in comparison with the wild-type strain (202 were upregulated, and 167 were downregulated). The loss-of-function mutation in hfq led to pleiotropic phenotypic effects, including an altered bacterial growth rate and reduced adherence to epithelial cells. Twitching motility and microcolony formation were not affected. Hfq also appears to play a minor role in inducing the inflammatory response of infected human epithelial cells. Interleukin-8 production was slightly decreased, and activation of c-Jun N-terminal kinase, a mitogen-activated protein kinase, was reduced in MS11hfq- infected epithelial cells in comparison with wild type-infected cells. However, activation of nuclear factor kappa B, extracellular signal-regulated kinase 1/2 and p38 remained unchanged. The data presented suggest that Hfq plays an important role as a post-transcriptional regulator in N. gonorrhoeae strain MS11 but does not contribute significantly to its virulence in cell culture models. [source] A human-specific TNF-responsive promoter for Goodpasture antigen-binding proteinFEBS JOURNAL, Issue 20 2005Froilán Granero The Goodpasture antigen-binding protein, GPBP, is a serine/threonine kinase whose relative expression increases in autoimmune processes. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine implicated in autoimmune pathogenesis. Here we show that COL4A3BP, the gene encoding GPBP, maps head-to-head with POLK, the gene encoding for DNA polymerase kappa (pol ,), and shares with it a 140-bp promoter containing a Sp1 site, a TATA-like element, and a nuclear factor kappa B (NF,B)-like site. These three elements cooperate in the assembly of a bidirectional transcription complex containing abundant Sp1 and little NF,B that is more efficient in the POLK direction. Tumour necrosis factor cell induction is associated with Sp1 release, NF,B recruitment and assembly of a complex comparatively more efficient in the COL4A3BP direction. This is accomplished by competitive binding of Sp1 and NF,B to a DNA element encompassing a NF,B-like site that is pivotal for the 140-bp promoter to function. Consistently, a murine homologous DNA region, which contains the Sp1 site and the TATA-like element but is devoid of the NF,B-like site, does not show transcriptional activity in transient gene expression assays. Our findings identify a human-specific TNF-responsive transcriptional unit that locates GPBP in the signalling cascade of TNF and substantiates previous observations, which independently related TNF and GPBP with human autoimmunity. [source] Nuclear factor-kappaB as a molecular target for migraine therapy.HEADACHE, Issue 4 2003U Reuter Ann Neurol. 2002;51:507-516. Nitric oxide (NO) generated from inducible NO synthase (iNOS) participates in immune and inflammatory responses in many tissues. The NO donor glyceryl trinitrate (GTN) provokes delayed migraine attacks when infused into migraineurs and also causes iNOS expression and delayed inflammation within rodent dura mater. Sodium nitroprusside, an NO donor as well, also increases iNOS expression. Because inflammation and iNOS are potential therapeutic targets, we examined transcriptional regulation of iNOS following GTN infusion and the consequences of its inhibition within dura mater. We show that intravenous GTN increases NO production within macrophages. L-N(6)-(1-iminoethyl)lysine, a selective iNOS inhibitor, attenuates the NO signal, emphasizing the importance of enzymatic activity to delayed NO production. iNOS expression is preceded by significant nuclear factor kappa B (NF-kappaB) activity, as reflected by a reduction in the inhibitory protein-kappa-Balpha (IkappaBalpha) and activation of NF-kappaB after GTN infusion. IkappaBalpha degradation, NF-kappaB activation, and iNOS expression were attenuated by parthenolide (3mg/kg), the active constituent of feverfew, an anti-inflammatory drug used for migraine treatment. These findings suggest that GTN promotes NF-kappaB activity and inflammation with a time course consistent with migraine attacks in susceptible individuals. We conclude, based on results with this animal model, that blockade of NF-kappaB activity provides a novel transcriptional target for the development of anti-migraine drugs. Comment: This paper suggesting the localization of NO production in dural macrophages as part of delayed inflammation may indicate proliferation and or recruitment of these cells in migraine. Could this also be a target for drug treatment? Specifically, is the genetic transcription that leads to nitric oxide generation such a target? To amend slightly the old advertising slogan, "when Michael Moskowitz talks, we all listen." DSM and SJT [source] Signalling events involved in interferon-,-inducible macrophage nitric oxide generationIMMUNOLOGY, Issue 4 2003Julie Blanchette Summary Nitric oxide (NO) produced by macrophages (M,) in response to interferon-, (IFN-,) plays a pivotal role in the control of intracellular pathogens. Current knowledge of the specific biochemical cascades involved in this IFN-,-inducible M, function is still limited. In the present study, we evaluated the participation of various second messengers , Janus kinase 2 (JAK2), signal transducer and activator of transcription (STAT) 1,, MAP kinase kinase (MEK1/2), extracellular signal-regulated kinases 1 and 2 (Erk1/Erk2) and nuclear factor kappa B (NF-,B) , in the regulation of NO production by IFN-,-stimulated J774 murine M,. The use of specific signalling inhibitors permitted us to establish that JAK2/STAT1,- and Erk1/Erk2-dependent pathways are the main players in IFN-,-inducible M, NO generation. To determine whether the inhibitory effect was taking place at the pre- and/or post-transcriptional level, we evaluated the effect of each antagonist on inducible nitric oxide synthase (iNOS) gene and protein expression, and on the capacity of IFN-, to induce JAK2, Erk1/Erk2 and STAT1, phosphorylation. All downregulatory effects occurred at the pretranscriptional level, except for NF-,B, which seems to exert its role in NO production through an iNOS-independent event. In addition, electrophoretic mobility shift assay (EMSA) analysis revealed that STAT1, is essential for IFN-,-inducible iNOS expression and NO production, whereas the contribution of NF-,B to this cellular regulation seems to be minimal. Moreover, our data suggest that Erk1/Erk2 are responsible for STAT1, Ser727 residue phosphorylation in IFN-,-stimulated M,, thus contributing to the full activation of STAT1,. Taken together, our results indicate that JAK2, MEK1/2, Erk1/Erk2 and STAT1, are key players in the IFN-,-inducible generation of NO by M,. [source] Bifidobacterium lactis inhibits NF-,B in intestinal epithelial cells and prevents acute colitis and colitis-associated colon cancer in mice,,INFLAMMATORY BOWEL DISEASES, Issue 9 2010Seung Won Kim MS Abstract Background: The aim of this study was to investigate the antiinflammatory effects of Bifidobacterium lactis on intestinal epithelial cells (IECs) and on experimental acute murine colitis and its tumor prevention effects on colitis-associated cancer (CAC) in mice. Methods: Human HT-29 cells were stimulated with IL-1,, lipopolysaccharides, or tumor necrosis factor-, with and without B. lactis, and the effects of B. lactis on nuclear factor kappa B (NF-,B) signaling in IEC were examined. For in vivo study, dextran sulfate sodium (DSS)-treated mice were fed with and without B. lactis. Finally, we induced colonic tumors in mice by azoxymethane (AOM) and DSS and evaluated the effects of B. lactis on tumor growth. Results: B. lactis significantly suppressed NF-,B activation, including NF-,B-binding activity and NF-,B-dependent reporter gene expression in a dose-dependent manner, and suppressed I,B-, degradation, which correlated with the downregulation of NF-,B-dependent gene products. Moreover, B. lactis suppressed the development of acute colitis in mice. Compared with the DSS group, the severity of DSS-induced colitis as assessed by disease activity index, colon length, and histological score was reduced in the B. lactis -treated group. In the CAC model, the mean number and size of tumors in the B. lactis -treated group were significantly lower than those in the AOM group. Conclusions: Our data demonstrate that B. lactis inhibits NF-,B and NF-,B-regulated genes in IEC and prevents acute colitis and CAC in mice. These results suggest that B. lactis could be a potential preventive agent for CAC as well as a therapeutic agent for inflammatory bowel disease. (Inflamm Bowel Dis 2010) [source] Astaxanthin protects mesangial cells from hyperglycemia-induced oxidative signaling,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Emiko Manabe Abstract Astaxanthin (ASX) is a carotenoid that has potent protective effects on diabetic nephropathy in mice model of type 2 diabetes. In this study, we investigated the protective mechanism of ASX on the progression of diabetic nephropathy using an in vitro model of hyperglycemia, focusing on mesangial cells. Normal human mesangial cells (NHMCs) were cultured in the medium containing normal (5 mM) or high (25 mM) concentrations of D -glucose. Reactive oxygen species (ROS) production, the activation of nuclear transcription factors such as nuclear factor kappa B (NF,B) and activator protein-1 (AP-1), and the expression/production of transforming growth factor-beta 1 (TGF,1) and monocyte chemoattractant protein-1 (MCP-1) were evaluated in the presence or absence of ASX. High glucose (HG) exposure induced significant ROS production in mitochondria of NHMCs, which resulted in the activation of transcription factors, and subsequent expression/production of cytokines that plays an important role in the mesangial expansion, an important event in the pathogenesis of diabetic nephropathy. ASX significantly suppressed HG-induced ROS production, the activation of transcription factors, and cytokine expression/production by NHMCs. In addition, ASX accumulated in the mitochondria of NHMCs and reduced the production of ROS-modified proteins in mitochondria. ASX may prevent the progression of diabetic nephropathy mainly through ROS scavenging effect in mitochondria of mesangial cells and thus is expected to be very useful for the prevention of diabetic nephropathy. J. Cell. Biochem. 103: 1925,1937, 2007. © 2007 Wiley-Liss, Inc. [source] New concepts regarding focal adhesion kinase promotion of cell migration and proliferationJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Braden D. Cox Abstract Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that plays a key role in the regulation of proliferation and migration of normal and tumor cells. FAK associates with integrin receptors and recruits other molecules to the site of this interaction thus forming a signaling complex that transmits signals from the extracellular matrix to the cell cytoskeleton. Crk-associated substrate (CAS) family members appear to play a pivotal role in FAK regulation of cell migration. Cellular Src bound to FAK phosphorylates CAS proteins leading to the recruitment of a Crk family adaptor molecule and activation of a small GTPase and c-Jun N-terminal kinase (JNK) promoting membrane protrusion and cell migration. The relocalization of CAS and signaling through specific CAS family members appears to determine the outcome of this pathway. FAK also plays an important role in regulating cell cycle progression through transcriptional control of the cyclin D1 promoter by the Ets B and Kruppel-like factor 8 (KLF8) transcription factors. FAK regulation of cell cycle progression in tumor cells requires Erk activity, cyclin D1 transcription, and the cyclin-dependent kinase (cdk) inhibitor p27Kip1. The ability of FAK to integrate integrin and growth factor signals resulting in synergistic promotion of cell migration and proliferation, and its potential regulation by nuclear factor kappa B (NF,B) and p53 and a ubiquitously expressed inhibitory protein, suggest that it is remarkable in its capacity to integrate multiple extracellular and intracellular stimuli. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-,-treated human aortic endothelial cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2001Yung-Hsiang Chen Abstract Attachment to, and migration of leukocytes into the vessel wall is an early event in atherogenesis. Expression of cell adhesion molecules by the arterial endothelium may play a major role in atherosclerosis. It has been suggested that antioxidants inhibit the expression of adhesion molecules and may thus attenuate the processes leading to atherosclerosis. In the present study, the effects of a potent water-soluble antioxidant, salvianolic acid B (Sal B), and an aqueous ethanolic extract (SME), both derived from a Chinese herb, Salvia miltiorrhiza, on the expression of endothelial-leukocyte adhesion molecules by tumor necrosis factor-, (TNF-,)-treated human aortic endothelial cells (HAECs) were investigated. When pretreated with SME (50 and 100 ,g/ml), the TNF-,-induced expression of vascular adhesion molecule-1 (VCAM-1) was notably attenuated (77.2,±,3.2% and 80.0,±,2.2%, respectively); and with Sal B (1, 2.5, 5, 10, and 20 ,g/ml), 84.5,±,1.9%, 78.8,±,1.2%, 58.9,±,0.4%, 58.7,±,0.9%, and 57.4,±,0.3%, respectively. Dose-dependent lowering of expression of intercellular cell adhesion molecule-1 (ICAM-1) was also seen with SME or Sal B. In contrast, the expression of endothelial cell selectin (E-selectin) was not affected. SME (50 ,g/ml) or Sal B (5 ,g/ml) significantly reduced the binding of the human monocytic cell line, U937, to TNF-,-stimulated HAECs (45.7,±,2.5% and 55.8,±,1.2%, respectively). SME or Sal B significantly inhibited TNF-,-induced activation of nuclear factor kappa B (NF-,B) in HAECs (0.36- and 0.48-fold, respectively). These results demonstrate that SME and Sal B have anti-inflammatory properties and may explain their anti-atherosclerotic properties. This new mechanism of action of Sal B and SME, in addition to their previously reported inhibition of LDL, may help explain their efficacy in the treatment of atherosclerosis. J. Cell. Biochem. 82:512,521, 2001. © 2001 Wiley-Liss, Inc. [source] 17,-oestradiol up-regulates longevity-related, antioxidant enzyme expression via the ERK1 and ERK2[MAPK]/NF,B cascadeAGING CELL, Issue 3 2005Consuelo Borrás Summary Females live longer than males. Oestrogens protect females against aging by up-regulating the expression of antioxidant, longevity-related genes such as glutathione peroxidase (GPx) and Mn-superoxide dismutase (Mn-SOD). The mechanism through which oestrogens up-regulate those enzymes remains unidentified, but may have implications for gender differences in lifespan. We show that physiological concentrations of oestradiol act through oestrogen receptors to reduce peroxide levels in MCF-7 cells (a mammary gland tumour cell line). Oestradiol increases MAP kinase (MAPK) activation as indicated by ERK1 and ERK2 phosphorylation in MCF-7 cells, which in turn activates the nuclear factor kappa B (NF,B) signalling pathways as indicated by an increase in the p50 subunit of NF,B in nuclear extracts. Blockade of MAPK and NF,B signalling reduces the antioxidant effect of oestradiol. Finally, we show that activation of MAPK and NF,B by oestrogens drives the expression of the antioxidant enzymes Mn-SOD and GPx. We conclude that oestradiol sequentially activates MAPK and NF,B following receptor activation to up-regulate the expression of antioxidant enzymes, providing a cogent explanation for the antioxidant properties of oestrogen and its effects on longevity-related genes. [source] Neurosteroid dehydroepiandrosterone exerts anti-apoptotic effects by membrane-mediated, integrated genomic and non-genomic pro-survival signaling pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Ioannis Charalampopoulos Abstract Dehydroepiandrosterone (DHEA) protects neural crest-derived PC12 cells from serum deprivation-induced apoptosis via G protein-associated specific plasma membrane-binding sites (mDBS). Here, we studied the signaling pathways involved in the pro-survival effects of DHEA-mediated activation of the mDBS binding sites. Membrane impermeable DHEA-bovine serum albumin (BSA) conjugate induced an acute phosphorylation of the prosurvival kinases Src, protein kinase A (PKA), MEK1/2/ERK1/2, and PI3K/Akt in serum deprived PC12 cells in parallel to an elevation of intracellular cAMP. The physiological significance of these findings was further assessed in a series of experiments using several selective pro-survival kinase inhibitors. Our combined findings suggest that the following sequence of events may take place following activation of mDBS binding sites: DHEA-BSA induces an acute but transient sequential phosphorylation of the pro-survival kinases Src/PKCa/b/MEK1/2/ERK1/2 which, in their turn, activate transcription factors cAMP responsive element binding protein and nuclear factor kappa B which induce the expression of the anti-apoptotic Bcl-2 genes. In parallel, DHEA-BSA increases intracellular cAMP, and the subsequent phosphorylation of PKA kinase and of cAMP responsive element binding protein. Finally, DHEA-BSA induces phosphorylation of PI3K/Akt kinases which, subsequently, lead to phosphorylation/deactivation of the pro-apoptotic Bad. Our findings suggest that the neurosteroid DHEA affects neural crest-derived cell survival by multiple pro-survival signaling pathways comprising an integrated system of non-genomic and genomic mechanisms. [source] Noradrenergic depletion increases inflammatory responses in brain: effects on I,B and HSP70 expressionJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Michael T. Heneka Abstract The inflammatory responses in many cell types are reduced by noradrenaline (NA) binding to ,-adrenergic receptors. We previously demonstrated that cortical inflammatory responses to aggregated amyloid beta (A,) are increased if NA levels were first depleted by lesioning locus ceruleus (LC) noradrenergic neurons, which replicates the loss of LC occurring in Alzheimer's disease. To examine the molecular basis for increased responses, we used the selective neurotoxin DSP4 to lesion the LC, and then examined levels of putative anti-inflammatory molecules. Inflammatory responses were achieved by injection of aggregated A,1,42 peptide and IL-1, into frontal cortex, which induced neuronal inducible nitric oxide synthase (iNOS) and microglial IL-1, expression. DSP4-treatment reduced basal levels of nuclear factor kappa B (NF-,B) inhibitory I,B proteins, and of heat shock protein (HSP)70. Inflammatory responses were prevented by co-injection (ibuprofen or ciglitzaone) or oral administration (pioglitazone) of peroxisome proliferator-activated receptor gamma (PPAR,) agonists. Treatment with PPAR, agonists restored I,B,, I,B,, and HSP70 levels to values equal or above those observed in control animals, and reduced activation of cortical NF-,B. These results suggest that noradrenergic depletion reduces levels of anti-inflammatory molecules which normally limit cortical responses to A,, and that PPAR, agonists can reverse that effect. These findings suggest one mechanism by which PPAR, agonists could provide benefit in neurological diseases having an inflammatory component. [source] The mechanisms underlying the anti-aging activity of the Chinese prescription Kangen-karyu in hydrogen peroxide-induced human fibroblastsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2005Akiko Satoh Our previous study showed that Kangen-karyu extract protected against cellular senescence by reducing oxidative damage through the inhibition of reactive oxygen species generation and regulation of the antioxidative status. Although these findings suggest that Kangen-karyu could delay the aging process, the mechanisms responsible for protection against aging have rarely been elucidated. Therefore, this study was focussed on the mechanisms responsible for the anti-aging activity of Kangen-karyu extract using hydrogen peroxide (H2O2)-induced human diploid fibroblasts, a well-established experimental model of cellular aging. Kangen-karyu extract exerted a protective effect against the morphological changes induced by H2O2 treatment and inhibited senescence-associated ,-galactosidase activity. In addition, the beneficial effects of Kangen-karyu extract on cell viability and lifespan indicated that Kangen-karyu extract could delay the cellular aging process. The observation that Kangen-karyu extract prevented nuclear factor kappa B (NF-,B) translocation in response to oxidative stress suggested that Kangen-karyu exerted its anti-aging effect through NF-,B modulation and prevention of H2O2 -induced overexpression of haem oxygenase-1 protein. Moreover, pretreatment with Kangen-karyu extract reduced overexpression of bax protein and prevented the mitochondrial membrane potential decline, suggesting that Kangen-karyu extract may protect mitochondria from mitochondrial oxidative stress and dysfunction. These findings indicate that Kangen-karyu is a promising potential anti-aging agent that may delay, or normalize, the aging process by virtue of its protective activity against oxidative stress-related conditions. [source] Crossregulation of NF-,B by the APC/GSK-3,/,-catenin pathwayMOLECULAR CARCINOGENESIS, Issue 3 2004Jiong Deng Abstract Glycogen synthase kinase-3, (GSK-3,) and adenomatous polyposis coli (APC) play an important role in the regulation of ,-catenin. Inhibition of or defects in their functions can lead to activation of ,-catenin. ,-catenin has been recently found to interact with and inhibit nuclear factor kappa B (NF-,B). However, the regulatory roles of GSK-3,/APC on the NF-,B signaling pathway are unknown because of their diverse effects. In this study, we investigated whether GSK-3,/APC might regulate NF-,B activity through ,-catenin. We found that inhibition of GSK-3, suppressed NF-,B activity, whereas reexpression of APC restored NF-,B activity in APC mutated cells. The regulatory effects were through ,-catenin because depletion of ,-catenin with small interfering RNA (siRNA) in the same systems reversed the effects. The regulatory relationship was further supported by the analysis of primary breast tumor tissues in vivo in which NF-,B target TRAF1 was inversely correlated with activated ,-catenin. Thus, APC/GSK-3,, through ,-catenin, may crossregulate NF-,B signaling pathway. © 2004 Wiley-Liss, Inc. [source] Protective effect of vitamin E on ultraviolet B light,induced damage in keratinocytesMOLECULAR CARCINOGENESIS, Issue 3 2002Samar Maalouf Abstract Ultraviolet (UV) B radiation is the most common environmental factor in the pathogenesis of skin cancer. Exposure of human skin to UVB radiation leads to the depletion of cutaneous antioxidants, the activation of nuclear factor kappa B (NF-,B), and programmed cell death (apoptosis). Although antioxidant supplementation has been shown to prevent UVB-induced photooxidative damage, its effect on components of cell signaling pathways leading to gene expression has not been clearly established. In the present study, the effect of the antioxidant vitamin, ,-tocopherol (,-T), and its acetate analog, ,-tocopherol acetate (,-TAc), on UVB-induced damage in primary and neoplastic mouse keratinocytes was investigated. The ability of both vitamins to modulate UVB-induced apoptosis and activation of the transcription factor NF-,B were studied. Treatment of normal and neoplastic mouse epidermal keratinocytes (308 cells) with 30,60 mJ/cm2 UVB markedly decreased viable cell number and was accompanied by DNA fragmentation. When both vitamins were applied to cells at times before and after UVB radiation, a significant increase in the percentage of viable cells and concomitant decrease in the number of apoptotic cells was noted, with vitamin pretreatment providing a better protection than posttreatment. Simultaneous posttreatment of irradiated cells with ,-TAc abolished the cytotoxic effects of UVB and restored cell viability to control levels. In addition, simultaneous posttreatment of irradiated cells with ,-T reduced the number of apoptotic cells by half, indicating a synergistic effect of two such treatments compared with any single one. Flow cytometry analysis indicated that vitamin treatment suppressed both an increase in pre-G0 cells and a decrease in cycling cells by UVB exposure. In addition, NF-,B activation was detected 2 h after UV exposure and was maintained for up to 8 h. Pretreatment with vitamins significantly inhibited NF-,B activation at 4 and 8 h. These results indicate that vitamin E and its acetate analog can modulate the cellular response to UVB partly through their action on NF-,B activation. Thus, these antioxidant vitamins are potential drugs for the protection from or the reduction of UVB-associated epidermal damage. © 2002 Wiley-Liss, Inc. [source] Proinflammatory signalling stimulated by the type III translocation factor YopB is counteracted by multiple effectors in epithelial cells infected with Yersinia pseudotuberculosisMOLECULAR MICROBIOLOGY, Issue 5 2003Gloria I. Viboud Summary Type III secretion systems are used by several pathogens to translocate effector proteins into host cells. Yersinia pseudotuberculosis delivers several Yop effectors (e.g. YopH, YopE and YopJ) to counteract signalling responses during infection. YopB, YopD and LcrV are components of the translocation machinery. Here, we demonstrate that a type III translocation protein stimulates proinflammatory signalling in host cells, and that multiple effector Yops counteract this response. To examine proinflammatory signalling by the type III translocation machinery, HeLa cells infected with wild-type or Yop,Y. pseudotuberculosis strains were assayed for interleukin (IL)-8 production. HeLa cells infected with a YopEHJ, triple mutant released significantly more IL-8 than HeLa cells infected with isogenic wild-type, YopE,, YopH, or YopJ, bacteria. Complementation analysis demonstrated that YopE, YopH or YopJ are sufficient to counteract IL-8 production. IL-8 production required YopB, but did not require YopD, pore formation or invasin-mediated adhesion. In addition, YopB was required for activation of nuclear factor kappa B, the mitogen-activated protein kinases ERK and JNK and the small GTPase Ras in HeLa cells infected with the YopEHJ, mutant. We conclude that interaction of the Yersinia type III translocator factor YopB with the host cell triggers a proinflammatory signalling response that is counteracted by multiple effectors in host cells. [source] IL1,- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn's diseaseNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2009M. Kidd Abstract, Gut mucosal enterochromaffin (EC) cells are regarded as key regulators of intestinal motility and fluid secretion via secretion of serotonin (5HT), are increased in numbers in mucosal inflammation and located in close proximity to immune cells. We examined whether interleukin (IL)1, and Escherichia coli lipopolysaccharide (LPS) induced EC cell 5HT release through Toll-like/IL-1 (TIL) receptor activation, nuclear factor kappa B (NF,B) and mitogen-activated protein kinase (MAPK) phosphorylation and evaluated whether somatostatin could inhibit this phenomenon. Pure (>98%) human intestinal EC cells were isolated by fluorescent activated cell sorting from preparations of normal (n = 5) and Crohn's colitis (n = 6) mucosa. 5HT release was measured (ELISA), and NF,B and ERK phosphorylation quantitated (ELISA) in response to IL1, and LPS. 5HT secretion was increased by both E. coli LPS (EC50 = 5 ng mL,1) and IL1, (EC50 = 0.05 pmol L,1) >2-fold (P < 0.05) in Crohn's EC cells compared with normal EC cells. Secretion was reversible by the TLR4 antagonist, E. coli K12 LPS (IC50 = 12 ng mL,1) and the IL1, receptor antagonist (ILRA; IC50 = 3.4 ng mL,1). IL1, caused significant (P < 0.05) NF,B and MAPK phosphorylation (40,55%). The somatostatin analogue, lanreotide inhibited IL1,-stimulated secretion in Crohn's (IC50 = 0.61 nmol L,1) and normal EC cells (IC50 = 1.8 nmol L,1). Interleukins (IL1,) and bacterial products (E. coli LPS) stimulated 5HT secretion from Crohn's EC cells via TIL receptor activation (TLR4 and IL1,). Immune-mediated alterations in EC cell secretion of 5HT may represent a component of the pathogenesis of abnormal bowel function in Crohn's disease. Inhibition of EC cell-mediated 5HT secretion may be an alternative therapeutic strategy in the amelioration of inflammatory bowel disease symptomatology. [source] Cyclooxygenase-2 Expression Induced by Photofrin Photodynamic Therapy Involves the p38 MAPK Pathway,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2008Marian Luna Photodynamic therapy (PDT), using the porphyrin photosensitizer Photofrin (PH), is approved for the clinical treatment of solid tumors. In addition to the direct cytotoxic responses of PH,PDT-mediated oxidative stress, this procedure also induces expression of angiogenic and prosurvival molecules including cyclooxygenase-2 (COX-2). In vivo treatment efficacy is improved when PH-PDT is combined with inhibitors of COX-2. In the current study we evaluated the signaling pathways involved with PH,PDT-mediated COX-2 expression in a mouse fibrosarcoma cell line. COX-2 promoter reporter constructs with mutated transcription elements documented that the nuclear factor kappa B (NF,B) element, cyclic-AMP response element 2 (CRE-2), CCAAT/enhancer binding protein (C/EBP) element and activator binding protein-1 (AP-1) element were responsive to PH-PDT. Transcription factor binding assays demonstrated that nuclear protein binding to NF,B, CRE-2, c-fos and c-jun elements were elevated following PH-PDT. Kinase phosphorylation upstream of COX-2 expression was also examined following PH-PDT. Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and c-Jun were phosphorylated following PH-PDT but the SAPK/JNK inhibitor SP600125 failed to attenuate COX-2 expression. In contrast, p38 mitogen-activated protein kinase (MAPK), which activates CRE-2 binding, was phosphorylated following PH-PDT and inhibitors of p38 MAPK, SB203580 and SB202190, decreased PH,PDT-induced COX-2 expression at both the mRNA and protein levels. Extracellular signal-regulated kinase (ERK1/2) phosphorylation, which also increases CRE-2 binding activity, was initially high in untreated cells, decreased immediately following PH-PDT and then rapidly increased. MEK1/2 is immediately upstream of ERK1/2 and the MEK1 inhibitor PD98059 failed to attenuate COX-2 expression while the MEK1/2 inhibitor U0126 induced a slight decrease in COX-2 expression. The NF,B inhibitor SN50 failed to reduce COX-2 expression. These results demonstrate that multiple protein kinase cascades can be activated by oxidative stress and that the p38 MAPK signaling pathway and CRE-2 binding are involved in COX-2 expression following PH-PDT. [source] Inhibition of UVB-mediated Oxidative Stress and Markers of Photoaging in Immortalized HaCaT Keratinocytes by Pomegranate Polyphenol Extract POMxPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2007Mohammad Abu Zaid In recent years there has been an increase in use of botanicals with antioxidant properties as skin photoprotective agents. Pomegranate (Punica granatum L.) fruit possesses strong antioxidant and antiinflammatory properties. Recently, we have shown that pomegranate-derived products rich in anthocyanidins and ellagitannins inhibit UVB-mediated activation of nuclear factor kappa B and modulate UVA-mediated cell proliferation pathways in normal human epidermal keratinocytes. In this study, we evaluated the effect of polyphenol-rich pomegranate fruit extract (POMx) on UVB-induced oxidative stress and photoaging in human immortalized HaCaT keratinocytes. Our data show that pretreatment of HaCaT cells with POMx (10,40 ,g mL,1) inhibited UVB (15,30 mJ cm,2)-mediated (1) decrease in cell viability, (2) decrease in intracellular glutathione content and (3) increase in lipid peroxidation. Employing immunoblot analysis we found that pretreatment of HaCaT cells with POMx inhibited UVB-induced (1) upregulation of MMP-1, -2, -7 and -9, (2) decrease in TIMP-1, (3) phosphorylation of MAPKs and (iv) phosphorylation of c-jun, whereas no effect was observed on UVB-induced c-fos protein levels. These results suggest that POMx protects HaCaT cells against UVB-induced oxidative stress and markers of photoaging and could be a useful supplement in skin care products. [source] Activation of HIV in Human Skin by Ultraviolet B Radiation and its Inhibition by NF,B Blocking Agents,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 6 2001Joan Breuer-McHam ABSTRACT To determine whether ultraviolet B (UVB) irradiation leads to activation of HIV in human skin, we conducted prospective and controlled studies in two academic medical centers in Texas from July 1995 to April 1999. HIV-positive patients with UV-treatable skin diseases were enrolled at each center, 18 subjects at one and 16 at the other. In one center, specimens from lesional and nonlesional skin biopsies were taken before and after sham- or UVB-irradiation administered in vivo or in vitro. In the other center, UVB phototherapy was administered three times weekly and specimens from skin biopsies were taken before and after 2 weeks (six treatments). Cutaneous HIV load was assessed using reverse transcriptase-polymerase chain reaction and reverse transcriptase-polymerase chain reaction in situ hybridization. UVB irradiation led to a 6,10-fold increase in the number of HIV in skin. To ascertain a role for nuclear factor kappa B (NF,B) in UVB-inducible HIV activation, two types of blockers, NF,B oligonucleotide decoy and sodium salicylate, were tested; each inhibited UVB-inducible HIV activation in skin partially. We conclude that UVB irradiation leads to increased numbers of HIV in human skin via processes that include release of cytoplasmic NF,B. [source] Synergistic inhibitory effect of sulforaphane and 5-fluorouracil in high and low metastasis cell lines of salivary gland adenoid cystic carcinomaPHYTOTHERAPY RESEARCH, Issue 3 2009Xiao-Feng Wang Abstract The present study aimed to evaluate the growth-inhibitory effect of sulforaphane (SFN) and a traditional chemotherapy agent, 5-fluorouracil (5-Fu), against the proliferation of salivary gland adenoid cystic carcinoma high metastatic cell line (ACC-M) and low metastasis cell line (ACC-2). Furthermore, the expression of nuclear factor kappa B (NF- ,B) which induces resistance to anticancer chemotherapeutic agents was also detected. The combination effect of SFN and 5-Fu was quantitatively determined using the method of median effect principle and the combination index. The nuclear NF- ,B p65 expression after treatment with the SFN-5-Fu combination was also evaluated by western blot analysis. The ACC-M and ACC-2 cells exhibited relative resistant to 5-Fu. Treatment ACCs cells with SFN and 5-Fu in combination, led to synergistic inhibition on cell growth and a decreased expression in nuclear NF- ,B p65 protein. This synergistic inhibitory effect was more significant in ACC-M cells, which is associated with the greatly decreased expression of NF- ,B p65 (almost 5-fold) after the combination treatment. Our results demonstrate synergism between SFN and 5-Fu at higher doses against the ACC-M and ACC-2 cells, which was associated with the decreased expression of nuclear NF- ,B p65 protein. Copyright © 2008 John Wiley & Sons, Ltd. [source] Thymoquinone decreases AGE-induced NF- ,B activation in proximal tubular epithelial cellsPHYTOTHERAPY RESEARCH, Issue 9 2007Ahmed Amir Radwan Sayed Abstract The inhibitory effects of thymoquinone (TQ) on activation of the redox-sensitive transcription factor nuclear factor kappa B (NF- ,B) and interleukin-6 (IL-6) were studied in vitro. Human proximal tubular epithelial cells (pTECs) were cultivated and stimulated with advanced glycation end products (AGEs) and the effects of TQ were studied. A significant reduction of AGE-induced NF- ,B-activation and Il-6 expression was observed. This points to potential antioxidative qualities of TQ. Copyright © 2007 John Wiley & Sons, Ltd. [source] Curcumin Suppresses the Paclitaxel-Induced Nuclear Factor-,B in Breast Cancer Cells and Potentiates the Growth Inhibitory Effect of Paclitaxel in a Breast Cancer Nude Mice ModelTHE BREAST JOURNAL, Issue 3 2009Hee Joon Kang MD Abstract:, Most anticancer agents activate nuclear factor kappa B (NF-,B), which can mediate cell survival, proliferation, and metastasis. Curcumin has been shown to inhibit the growth of various cancer cells, without toxicity to normal cells. The antitumor effects of curcumin could be due in part to the inactivation of NF-,B. We hypothesize that blocking NF-,B activity may augment paclitaxel cancer chemotherapy. In this study, we investigated whether the inactivation of NF-,B by curcumin would enhance the efficacy of paclitaxel for inhibiting breast cancer growth in vitro and in vivo. We confirmed that curcumin inhibited paclitaxel-induced activation of NF-,B and potentiated the growth inhibitory effect of paclitaxel in MDA-MB-231 breast cancer cells. The combination of curcumin with paclitaxel elicited significantly greater inhibition of cell growth and more apoptosis, compared with either agent alone. In an experimental breast cancer murine model using MDA-MB-231 cells, combination therapy with paclitaxel and curcumin significantly reduced tumor size and decreased tumor cell proliferation, increased apoptosis, and decreased the expression of matrix metalloprotease 9 compared with either agent alone. These results clearly suggest that a curcumin,paclitaxel combination could be a novel strategy for the treatment of breast cancer. [source] Osteoprotegerin in the Inner Ear May Inhibit Bone Remodeling in the Otic Capsule,THE LARYNGOSCOPE, Issue 1 2005Andreas F. Zehnder MD Abstract Objectives: To elucidate factors that may be responsible for the inhibition of remodeling of bone within the otic capsule. Methods: Expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa B (RANK), and RANK ligand (RANKL) were assayed in samples of bone obtained from the otic capsule, calvarium, and femur, and from the soft tissue within the cochlea using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) in mice. Immunostaining was used for histologic localization of the gene products. An enzyme-linked immunosorbent assay (ELISA) was used to quantify the amount of OPG within perilymph, serum, and cerebrospinal fluid. The micro-anatomy of the interface between the otic capsule and the fluid spaces of the cochlea was investigated by brightfield and phase-contrast microscopy and by three-dimensional reconstruction in the mouse and human. Results: OPG, a powerful inhibitor of bone remodeling, was expressed at extremely high levels within the soft tissue of the cochlea and was present in the perilymph at very high concentrations. The OPG produced within the inner ear may diffuse into the surrounding otic capsule, where it may be responsible for inhibition of bone turnover. Our anatomic studies revealed an extensive system of interconnected canaliculi within the otic capsule that had direct openings into the fluid spaces of the inner ear, thus providing a possible anatomic route for the diffusion of OPG from the inner ear into the surrounding bone. Conclusion: OPG, a potent inhibitor of osteoclast formation and function, is expressed at high levels within the inner ear and is secreted into the perilymph and the surrounding bone and may serve to inhibit active bone remodeling within the otic capsule, especially immediately adjacent to the cochlea. By this means, the cochlear soft tissue may control the nature of the surrounding petrous bone. [source] | ||||||||||||||||||||||||||||