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Tumor Necrosis Factor (tumor + necrosis_factor)
Kinds of Tumor Necrosis Factor Terms modified by Tumor Necrosis Factor Selected AbstractsQuantitative Analysis of Cytokine mRNA Expression in Hearts from Patients with Nonischemic Dilated Cardiomyopathy (DCM)JOURNAL OF CARDIAC SURGERY, Issue 2003Akira Ukimura To evaluate the role of cytokines in nonischemic DCM, we analyzed the relative quantity of cytokine mRNA expression in the hearts from DCM patients with refractory heart failure, using the ABI PRISM7700 real-time PCR system. We used heart tissues resected from 32 DCM patients at the time of elective partial ventriculectomy (PLV), and five biopsy specimens with normal histological findings as control. Results and Discussion: Interleukin (IL)-1,, IL-10, and Tumor Necrosis Factor (TNF)-, mRNA were expressed at low levels in all normal hearts. The number of IL-10-positive DCM cases was significantly smaller than normal controls (P = 0.0036). One (10%) of 10 DCM patients with IL-10 mRNA expression died after PLV, and 10 (45%) of 22 DCM patients without IL-10 mRNA expression died. IL-1, mRNA was overexpressed (over twice the mean of control subjects) in 15 of 32, and TNF-, mRNA in 10 of 32 patients. We propose the classification of DCM patients into subgroups on the basis of cytokine mRNA expression. Anticytokine therapy or cytokine therapy may have potential in improving the condition of heart failure in certain subgroups of DCM patients. Conclusions: We suggest that DCM patients with heart failure deteriorate without IL-10 mRNA expression in the myocardium. The classification of DCM patients into subgroups on the basis of cytokine mRNA expression may have great value in considering the treatment of this heterogeneous disease state. (J CARD SURG 2003;18 (Suppl 2):S101-S108) [source] Ethanol Increases the Neurotoxic Effect of Tumor Necrosis Factor- , in Cultured Rat AstrocytesALCOHOLISM, Issue 1 2000William J. DeVito Background: The central nervous system is particularly sensitive to the cytotoxic effect of ethanol. In vivo and in vitro studies indicate that ethanol decreases cell proliferation in a number of cells types, including neurons and glial cells in the central nervous system. The cellular mechanisms involved in ethanol-induced cell toxicity, however, are unclear. In this study, we examined the effect of ethanol on tumor necrosis factor- , (TNF,)-induced cell death in a homogeneous population of cultured rat astrocytes. Methods: Flow cytometric and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT) dye reduction analyses were performed on cultured rat astrocytes to determine the effect of alcohol on TNF, -induced cell death. Results: Flow cytometric analysis revealed that, in quiescent astrocytes, high concentrations of ethanol were required to increase DNA fragmentation and decrease cell viability. Preexposure of astrocytes to low concentrations of ethanol (10 to 50 mM), however, increased the sensitivity of astrocytes to TNF, with low TNF, concentrations (25 to 50 ng/ml) resulting in increased DNA fragmentation. Furthermore, MTT dye reduction analysis revealed that exposure of astrocytes to 5 mM ethanol was sufficient to increase the susceptibility of astrocytes to the cytotoxic effect of ethanol. In a number of cell types, TNF, receptor binding results in the activation of specific signal transduction cascades, including the hydrolysis of sphingomyclin to ceramide. We show that preexposure of astrocytes to a low concentration of ethanol increased the sensitivity of astrocytes to sphingomyelinase, and C2 -ceramide resulting in increased DNA fragmentation and decreased cell viability. More importantly, astrocytes prepared from rats exposed to ethanol prenatally showed increased susceptibility to TNF, -induced cell death. Conclusions: These studies suggest that ethanol increases the susceptibility of astrocytes to TNF, -induced cell death by shifting the balance of sphingolipid metabolism in favor of a pathway that increases the susceptibility of astrocytes to the cytotoxic effect of TNF,. [source] ORIGINAL ARTICLE: Endogenous Adenosine Down-Modulates Mid-Trimester IntraAmniotic Tumor Necrosis Factor-, ProductionAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 4 2009Uma Perni Problem, To determine whether adenosine in amniotic fluid down-regulates pro-inflammatory cytokine production. Method of study, Mid-trimester amniotic fluid from 21 women was incubated ex vivo in the presence or absence of human adenosine deaminase, the enzyme that irreversibly degrades adenosine. After 24 hr, supernatants were assayed by ELISA for tumor necrosis factor-, (TNF-,), interleukin (IL)-6, and IL-10. Clinical parameters were obtained after completion of laboratory testing. Results, Inclusion of adenosine deaminase resulted in a median increase in TNF-, production from 0.9 to 7.3 pg/mL (P = 0.0014). IL-6 production exhibited a non-significant median increase from <2.0 to 53.0 pg/mL (P = 0.0780). Median IL-10 production increased slightly from a median of <0.2 to 1.3 pg/mL. Adenosine deaminase-stimulated TNF-, production was proportional to parity and unrelated to gestational age, time of delivery, maternal age or indication for amniocentesis. Conclusion, Adenosine deaminase treatment increases TNF-, production by ex vivo -cultured amniotic fluid. Adenosine contributes to immune modulation in the amniotic cavity. [source] ORIGINAL ARTICLE: Tumor Necrosis Factor-,-Associated Mechanisms Affecting the Embryonic Response to CyclophosphamideAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2009Keren Mammon Problem, We have previously shown that TNF-,,/, embryos are more sensitive to the exposure to cyclophosphamide (CP) compared with TNF-,+/+ embryos; however, the underlying mechanisms are not fully understood. Thus, in our present study, we tried to identify those molecules that might be responsible for the protective effect of the cytokine. Method of study, CP-treated TNF-,,/, and TNF-,+/+ embryos were analyzed for changes in apoptosis by TUNEL and flow cytometry, while cell proliferation was analyzed by BrdU incorporation. The expression of Bax, bcl-2, p53, the p65 subunit of NF-,B and I,B, was assessed by Western blotting and immunohistochemistry. Results, CP-treated TNF-,,/, embryos exhibited a more profound decrease in their weight, which was accompanied by an earlier appearance of cellular damage and apoptotic cells and an earlier decrease in cell proliferation in the embryonic brain compared with TNF-,+/+ embryos. Also, an increased percentage of Bax-positive cells and a decreased percentage of bcl-2-positive cells were detected in TNF-,,/, embryos 48 hr after exposure, which were accompanied by a decreased percentage of p53-positive cells. Conclusion, Our data implicate TNF-, to be involved in the protection of the embryo against CP teratogenicity, possibly via alteration in Bax, bcl-2 or p53 expression. [source] Actions of Tumor Necrosis Factor-, on Oocyte Maturation and Embryonic Development in Cattle,AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2003P. Soto Problem:, Infertility can accompany mastitis in cattle. Involvement of tumor necrosis factor- , (TNF- ,) in this phenomenon is suggested by observations that circulating concentrations of TNF- , are elevated after intramammary infection or infusion of endotoxin. It was hypothesized that (1) TNF- , acts on the oocyte during maturation to decrease the percent of oocytes that cleave and develop following fertilization; (2) exposure of embryos to TNF- , after fertilization reduces development to the blastocyst stage; and (3) TNF- , increases the proportion of blastomeres that undergo apoptosis in a stage-of-development dependent manner. Method of study:, In one experiment, oocytes were matured with various concentrations of TNF- , and then fertilized and cultured without TNF- ,. In another study, embryos were cultured with TNF- , for 8 days beginning after fertilization. Finally, embryos were collected at the two or four-cell stage (at 28,30 hr after insemination) or when ,9-cells (at day 4 after insemination) and cultured ± TNF- , for 24 hr. The proportion of blastomeres undergoing apoptosis was then determined by the TUNEL procedure. Results:, Addition of TNF- , to maturation medium did not affect the proportion of oocytes that cleaved. However, the percent of oocytes that developed to the blastocyst stage at day 8 after insemination was reduced (P = 0.05) at all TNF- , concentrations tested (0.1,100 ng/mL). When added during embryo culture, there was no significant effect of TNF- , on the proportion of oocytes that became blastocysts. In addition, TNF- , did not induce apoptosis in two and four-cell embryos. For embryos ,9-cells, however, 10 and 100 ng/mL TNF- , increased (P < 0.05) the percent of blastomeres labeling as TUNEL-positive. Conclusion:, TNF- , can have deleterious actions on oocyte maturation that compromise development of the resultant embryo. While exposure of fertilized embryos to TNF- , did not inhibit development to the blastocyst stage, TNF- , increased the percentage of blastomeres undergoing apoptosis when exposure occurred for embryos ,9-cells. Increased blastomere apoptosis could conceivably compromise subsequent embryo survival. [source] Effect of Inhibitor of Tumor Necrosis Factor-, and Oxatomide on Immune Mediated Otitis MediaTHE LARYNGOSCOPE, Issue 9 2006Yong-Soo Park MD Abstract Objective: Inflammatory mediators (IMs) play a major role in the production of middle ear effusion (MEE). Tumor necrosis factor (TNF)-, and leukotrienes (LTs) appear to be important in the pathogenesis of otitis media with effusion (OME). The purpose of this study is to determine the effect of TNF-, and LT antagonist on the outcome of experimental immune-mediated OME. Study Design: Prospective. Methods: Otitis media was induced in rats by injecting keyhole limpet hemocyanin (KLH) transtympanically 7 days after systemic immunization. Experimental groups were treated with soluble TNF receptor type I (sTNF RI) or oxatomide simultaneously. Seventy-two hours after transtympanic injection, MEE was aspirated, and temporal bone was taken. Vascular permeability (VP) of the middle ear mucosa was measured using the Evans blue dye technique. Hematoxylin-eosin stain and immunohistochemical stain for leukocyte common antigen was performed. Results: In KLH, sTNF RI, and oxatomide groups, MEE was developed in 83%, 0%, and 66% of the ears, respectively. The sTNF RI group showed significant decrease in effusion production, inflammation, mucosal thickening, and VP compared with the KLH group. These parameters were less significant in the oxatomide group than in the sTNF RI group. Conclusion: Transtympanic administration of sTNF RI and oxatomide appears to suppress the development of immune-mediated MEE. [source] Clinical responses to tumor necrosis factor , antagonists do not show a bimodal distribution: Data from the Stockholm Tumor Necrosis Factor , Followup RegistryARTHRITIS & RHEUMATISM, Issue 6 2003Ronald F. van Vollenhoven Objective To study the distribution of clinical responses to treatment with the tumor necrosis factor , (TNF,) antagonists etanercept and infliximab, and in particular, to determine whether there is a biologically meaningful distinction between responders and nonresponders. Methods Among patients in the Stockholm TNF, Followup Registry, we analyzed the clinical responses to etanercept and infliximab, using the American College of Rheumatology (ACR) core set of outcome measures. For each parameter, the absolute change (value at baseline , current value) and the percentage change ([absolute change]/[value at baseline] × 100) from baseline were calculated. The results were plotted as histograms and inspected visually, and the distributions were statistically compared with computer-generated normal distributions. Results Absolute and relative changes in outcomes on the ACR core set of measures in 406 patients receiving etanercept or infliximab were studied. All but a few of these analyses yielded normal or somewhat skewed distributions. The statistical analyses did not detect any non-normal distributions, and visually, the distributions did not appear to be bimodal. Conclusion The clinical response to TNF, blockade displays a normal or skewed, but not bimodal, distribution. The frequently encountered perception that a clear distinction can be made between responders and nonresponders is not borne out. These relatively straightforward findings imply that the biologic mechanisms determining responsiveness to TNF, blockade are multifactorial and may also have important implications for regulatory guidelines pertaining to treatment with these biologic agents. [source] Synergistic Suppressive Effect of Double Transfection of Tumor Necrosis Factor-, and Interleukin 12 Genes on Tumorigenicity of Meth-A CellsCANCER SCIENCE, Issue 12 2000Hitoshi Fujiwara Tumor necrosis factor-,(TNF-,) and interleukin 12 (IL-12), both potent antitumor cytokines, are known to be involved in the host's antitumor immune surveillance in tumor bearers, via different mechanisms. The former enhances the activities of dendritic cells, natural killer/lymphocyteactivated killer (NK/LAK) and cytotoxic T lymphocyte (CTL), while the latter induces Th1-type cellular immunity and enhances the activities of natural killer T (NKT), NK/LAK and CTL. In the present study, in the expectation of synergistic actions of these cytokines in stimulating the host's immune responses, we investigated the feasibility of a cancer vaccine involving double transfection with both genes in a murine model. The expression of major histocompatibility complex (MHC) class I, class II and B7.1 on the surface of the double transfectants was enhanced as revealed by FACS analysis. A significant decrease in tumorigenicity was observed in mice inoculated with the double transfectants. Cytotoxicity assay revealed that the activities of NK/LAK and CTL from spleens of mice bearing the double transfectants were enhanced. The induction of tumor-specific immunity was confirmed by rechallenge with parental Meth-A cells in mice that had rejected the double transfectants. Thus, double transfection of TNF-,and IL-12 genes was considered to bring about synergistic suppressive effects on the tumorigenicity of transfectants through the activation of killer cells by produced cytokines and the enhancement of expression of MHC class I, II and B7.1 molecules. [source] Discovery of Selective Phosphonamide-Based Inhibitors of Tumor Necrosis Factor-, Converting Enzyme (TACE).CHEMINFORM, Issue 39 2003Masaaki Sawa Abstract For Abstract see ChemInform Abstract in Full Text. [source] The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkersEUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2009M. Khademi Background:, Natalizumab affects systemic cytokine expressions and clinical course in relapsing,remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients. Methods:, mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA. Results:, Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon-, (IFN-,) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-, and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. Conclusions:, Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy. [source] Natural killer cell proliferation and circulating cytokines in patients with bilateral basal ganglia calcificationEUROPEAN JOURNAL OF NEUROLOGY, Issue 5 2002T. Morishima Ten adult patients with symmetrical calcifications in the bilateral basal ganglia (diagnosed as physiological calcifications) were analyzed for lymphocyte subsets and cytokines. Increased number of natural killer (NK) cells were identified in the peripheral blood of seven patients by lymphocyte subset analysis. Tumor necrosis factor- , was detected in the sera of five patients and interferon- , was detected in one patient. In summary, NK cell propagation and circulating cytokines, particularly tumor necrosis factor- ,, may be involved in the etiology of basal ganglia calcification. [source] Catalytic digestion of human tumor necrosis factor-, by antibody heavy chainFEBS JOURNAL, Issue 18 2010Emi Hifumi It has long been an important task to prepare a catalytic antibody capable of digesting a targeting crucial protein that controls specific life functions. Tumor necrosis factor-, (TNF-,) is a cytokine and an important molecule concerned with autoimmune diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease, and Crohn's disease. A mAb (ETNF-6 mAb) raised against human TNF-, was prepared, and the steric conformation was created by using molecular modeling after the cDNA was sequenced. The heavy chain (ETNF-6-H) of the mAb was considered to possess a catalytic triad-like structure in the complementarity determining regions (CDRs). As a result, ETNF-6-H exhibited a peptidase and a protease activity. In fact, ETNF-6-H predominantly cleaved the Ser5-Arg6 bond of TNF-, at the first step, resulting in the generation of a fragment of , 17 kDa. This fragment was digested to a smaller molecule of 15 kDa by scission of the Gln21-Ala22 bond. The intermediate product was further converted into a fragment of 13.3 kDa by successive cleavage of the Leu36-Leu37 and Asn39-Gly40 bonds. The heavy chain possessed a protease activity against TNF-, with a multicleavage site. [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] Mitogen-activated protein kinases regulate Mycobacterium avium -induced tumor necrosis factor-, release from macrophagesFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2002Asima Bhattacharyya Abstract Tumor necrosis factor-, (TNF-,) is one of the key cytokines elicited by host macrophages upon challenge with pathogenic mycobacteria. Infection of human peripheral blood mononuclear cells or the murine macrophage cell line J774A,1 with Mycobacterium avium induced activation of the mitogen-activated protein kinases (MAPKs) ERK1/2, p38 and c-Jun N-terminal kinase. U0126, an MEK-specific inhibitor, abrogated M. avium -induced TNF-, secretion. Transfection of cells with dominant-negative MEK1 led to the suppression of TNF-, release in M. avium -challenged macrophages. M. avium activated p38 MAPK and use of the p38 MAPK inhibitor, SB203580, revealed that the p38 signaling pathway negatively regulates activation of ERK1/2 and release of TNF-,. Taken together, these results provide evidence that M. avium -induced TNF-, release from macrophages depends on an interplay between the ERK1/2 and the p38 MAPK signaling pathways. [source] Tumor necrosis factor is required for RANTES-induced astrocyte monocyte chemoattractant protein-1 productionGLIA, Issue 2 2003Yi Luo Abstract Astrocytes respond to stimulation with the chemokine RANTES (regulated on activation, normal T cell expressed) by production of a series of cytokines and chemokines, including tumor necrosis factor-, (TNF-,) and monocyte chemoattractant protein-1 (MCP-1). In the present study we demonstrate that RANTES induces TNF, which in turn stimulates subsequent production of MCP-1. TNF-R1 (p55) serves as the principal receptor responsible for MCP-1 synthesis. The results define an astrocyte proinflammatory cascade that amplifies synthesis of proinflammatory mediators. The implications of these findings to inflammatory diseases of the central nervous system are discussed. © 2003 Wiley-Liss, Inc. [source] Inhibition of Proinflammatory Cytokine Expression by NF-,B (p65) Antisense Oligonucleotide in Helicobacter pylori -Infected MiceHELICOBACTER, Issue 6 2005Sang Gyun Kim ABSTRACT Background.,Helicobacter pylori induces the expression of proinflammatory cytokines in vitro by activating nuclear factor-,B, a transcriptional regulator. However, it has not been clarified whether H. pylori -induced proinflammatory cytokines are also mediated through nuclear factor-,B in vivo. The aim of this study was to evaluate the role of nuclear factor-,B on the expressions of proinflammatory cytokines in H. pylori -infected mice. Materials and Methods., We evaluated nuclear factor-,B (p65) activation in the H. pylori -infected gastric mucosa of mice by immunofluorescent staining using antip65 polyclonal antibody, and the expressions of proinflammatory cytokines with inhibition of nuclear factor-,B pathway by using phosphorothioate antisense and sense oligonucleotide against the nuclear factor-,B (p65). Results., In the H. pylori -infected gastric mucosa of mice, immunofluorescent staining using antip65 polyclonal antibody showed nuclear factor-,B (p65) activation, which was particularly localized to epithelial cells. Tumor necrosis factor-, and interleukin-1, concentrations in gastric mucosa by enzyme-linked immunosorbent assay (ELISA) were elevated in the infected group versus the uninfected group. Pretreatment with nuclear factor-,B (p65) antisense oligonucleotide inhibited the activation of nuclear factor-,B and the expressions of tumor necrosis factor-, and interleukin-1, in H. pylori -infected gastric mucosa. Sense oligonucleotide did not influence on the expression of proinflammatory cytokines. Conclusions.,H. pylori infection was found to activate the expressions of proinflammatory cytokines via nuclear factor-,B in vivo, and this may play an important role in the initiation of H. pylori- induced gastric inflammation. [source] Tumor necrosis factor,like weak inducer of apoptosis is a mitogen for liver progenitor cells,,HEPATOLOGY, Issue 1 2010Janina E. E. Tirnitz-Parker Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor,like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin,positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NF,B) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NF,B subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NF,B-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (HEPATOLOGY 2010) [source] Increased tumor necrosis factor ,,converting enzyme activity induces insulin resistance and hepatosteatosis in mice,HEPATOLOGY, Issue 1 2010Loredana Fiorentino Tumor necrosis factor ,,converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C2C12 myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3,/, mice have higher TACE activity compared with wild-type (WT) mice. Timp3,/, mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3,/, liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N -methyltransferase and higher levels of liver fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3,/, compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE,Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice. (HEPATOLOGY 2009.) [source] Increased hepatotoxicity of tumor necrosis factor,related apoptosis-inducing ligand in diseased human liver,HEPATOLOGY, Issue 5 2007Xandra Volkmann Tumor necrosis factor,related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases. (HEPATOLOGY 2007.) [source] Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver,HEPATOLOGY, Issue 6 2005Yosuke Osawa Tumor necrosis factor (TNF) receptor, and Fas-mediated apoptosis are major death processes of hepatocytes in liver disease. Although antiapoptotic effects in the injured liver promote chronic hepatitis and carcinogenesis, scant information is known about these mechanisms. To explore this issue, we compared acute liver injury after TNF-, or anti-Fas antibody (Jo2) between livers from sham-operated mice and chronic injured liver via bile duct ligation (BDL). BDL inhibited hepatocyte apoptosis induced by TNF-, but not by Jo2. On the other hand, BDL inhibited the massive hemorrhage seen in livers treated with either TNF-, or Jo2. Inactivation of AKT blocked the antiapoptotic effect of BDL. Sphingosine kinase knockout mice also lost the antihemorrhagic effect of BDL and attenuated the antiapoptotic effects of BDL. In bile duct,ligated livers, hepatic stellate cells (HSCs) were activated and produced tissue inhibitor of metalloproteinase 1 in a sphingosine kinase (SphK)-1,dependent mechanism. In conclusion, BDL exerts antiapoptotic effects that appear to require activation of AKT in hepatocytes and SphK in HSCs.(HEPATOLOGY 2005;42:1320,1328.) [source] Low-dose TNF-, protects against hepatic ischemia-reperfusion injury in mice: Implications for preconditioningHEPATOLOGY, Issue 1 2003Narci Teoh Tumor necrosis factor , (TNF-,) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia-reperfusion (IR) liver injury and is associated with activation of nuclear factor ,B (NF-,B) and cell cycle entry. We examined the pattern of TNF-, release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low-dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naïve mice, hepatic and plasma levels of TNF-, rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF-, levels, but, during a second prolonged ischemic interval peak, TNF-, values were lower than in naïve mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 ,g or 5 ,g/kg body weight TNF-, 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF-, pretreatment activated NF-,B DNA binding, STAT3, cyclin D1, cyclin-dependent kinase 4 (cdk4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of "preconditioning" can be simulated by TNF-, injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF-, levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury. [source] Expression, regulation, and function of ,V integrins in hepatocellular carcinoma: An in vivo and in vitro studyHEPATOLOGY, Issue 2 2002Mimoun Nejjari The expression of ,V integrins by neoplastic cells contributes to the promotion of local invasion and metastasis. The most characteristic extracellular ligands of ,V integrins are vitronectin and fibronectin. Hepatocytes are the main source of vitronectin, and the capacity to synthesize and secrete vitronectin is usually retained in hepatocellular carcinoma. The aim of this study was to explore the expression, regulation, and functional role of ,V integrins in hepatocellular carcinoma. We first analyzed the expression of ,V integrins and their ligands fibronectin and vitronectin in 80 cases of hepatocellular carcinoma. ,V integrin chain was detected in 44 cases and vitronectin in 50. Twenty-four of the 44 ,V-positive tumors contained large amounts of vitronectin. These cases presented more frequently with adverse histoprognostic factors, including infiltrative growth pattern (62.5%), lack of capsule (71%), presence of capsular invasion (57%), and satellite nodules (50%). We then used HepG2 and Hep3B cell lines as in vitro models to study ,V integrin regulation and function. HepG2 and Hep3B cells expressed ,V integrin chain and used ,V,1 and ,V,5 for adhesion and migration on vitronectin. Tumor necrosis factor (TNF) , and transforming growth factor (TGF) , significantly increased the expression levels of ,V integrins and stimulated the adhesion and migration of both HepG2 and Hep3B cell lines on vitronectin. The effects of growth factors on cell adhesion and migration were reproduced by incubation with conditioned medium from rat liver myofibroblasts. In conclusion, our results support the existence of an ,V integrin/vitronectin connection in hepatocellular carcinoma and suggest that this connection may be an adverse prognostic factor. [source] Alcohol-induced free radicals in mice: Direct toxicants or signaling molecules?HEPATOLOGY, Issue 5 2001Ming Yin Tumor necrosis factor , (TNF-,) and free radicals are produced in early alcohol-induced liver injury. Recently, pathology caused by alcohol was blocked nearly completely in tumor necrosis factor , receptor 1 (TNF-R1) knockout mice. With this model, it is now possible to evaluate whether free radicals are directly toxic or act as redox regulators of TNF-, production. Specifically, if free radicals were directly toxic, a parallel decrease in free radicals and pathology in TNF-R1 knockout mice would be predicted. If they only affect TNF-, production, radicals would be expected to remain high while pathology is diminished. Accordingly, free radical production in TNF-R1 knockout mice was studied here. The enteral alcohol delivery model used mice lacking TNF-R1 (p55) and wild-type control C57Bl/6J mice. Animals received a liquid diet continuously with either ethanol or isocaloric maltose-dextrin as control for 4 weeks. Urine ethanol levels fluctuated from 10 to 500 mg/dL in a cyclic pattern in mice receiving ethanol. Ethanol elevated liver:body weight ratios, serum alanine transaminase (ALT) levels, and pathology scores in wild-type mice. These parameters were blunted nearly completely in TNF-R1 knockout mice. Ethanol treatment increased free radical production in wild-type mice compared with animals fed a high-fat control diet. There were no differences in intensity of free radical signals regardless of the presence or absence of TNF-R1; however, pathology differed markedly between these groups. These findings are consistent with the hypothesis that free radicals act as redox signals for TNF-, production and do not directly damage cells in early alcohol-induced hepatic injury. [source] Tumor necrosis factor-, augments lipopolysaccharide-induced suppressor of cytokine signalling 3 (SOCS-3) protein expression by preventing the degradationIMMUNOLOGY, Issue 1 2010Jargalsaikhan Dagvadorj Summary The regulatory role of tumour necrosis factor-, (TNF-,) on the expression of suppressor of cytokine signalling 3 (SOCS-3) in response to lipopolysaccharide (LPS) was examined using peritoneal macrophages from TNF-,-deficient mice. The LPS-induced SOCS-3 expression was markedly augmented in macrophages from wild-type mice whereas such augmentation was not seen in the cells from TNF-,-deficient mice. However, there was no significant difference in the level of SOCS-3 messenger RNA expression between macrophages from wild-type mice and those from TNF-,-deficient mice. The addition of exogenous TNF-, augmented the LPS-induced SOCS-3 expression in macrophages from TNF-,-deficient mice. The pulse chase analysis suggested augmented degradation of LPS-induced SOCS-3 protein in macrophages from TNF-,-deficient mice. Moreover, MG 132, a 26S proteasome inhibitor, sustained the LPS-induced SOCS-3 expression in those cells. The tyrosine phosphorylation of SOCS-3 was definitely induced in LPS-stimulated macrophages from TNF-,-deficient mice but not wild-type mice. A tyrosine phosphatase inhibitor enhanced the tyrosine phosphorylation of SOCS-3 in wild-type mice and accelerated the degradation. Therefore, it was suggested that TNF-, prevented the degradation of SOCS-3 protein via inhibition of the tyrosine phosphorylation in LPS-stimulated macrophages. [source] Medical therapy for Crohn's disease stricturesINFLAMMATORY BOWEL DISEASES, Issue 1 2004Gert Van Assche MD Abstract Intestinal fibrostenosis is a frequent and debilitating complication of Crohn's disease (CD), not only resulting in small bowel obstruction, but eventually in repeated bowel resection and short bowel syndrome. Over one third of patients with CD have a clear stenosing disease phenotype, often in the absence of luminal inflammatory symptoms. Intestinal fibrosis is a consequence of chronic transmural inflammation in CD. As in other organs and tissues, phenotypic transformation and activation of resident mesenchymal cells, such as fibroblasts and smooth muscle cells, underlie fibrogenesis in the gut. The molecular mechanisms and growth factors involved in this process have not been identified. However, it is clear that inflammatory mediators may have effects on mesenchymal cells in the submucosa and the muscle layers that are profoundly different from their action on leukocytes or epithelial cells. Transforming growth factor-beta (TGF-,), for instance, has profound anti-inflammatory activity in the mucosa and probably serves to keep physiologic inflammation at bay, but at the same time it appears to be driving the process of fibrosis in the deeper layers of the gut. Tumor necrosis factor, on the other hand, has antifibrotic bioactivity and pharmacologic inhibition of this cytokine carries a theoretical risk of enhanced stricture formation. Endoscopic management of intestinal strictures with balloon dilation is an accepted strategy to prevent or postpone repeated surgery, but careful patient selection is of paramount importance to ensure favorable long-term outcomes. Specific medical therapy aimed at preventing or reversing intestinal fibrosis is not yet available, but candidate molecules are emerging from research in the liver and in other organs. [source] Chronic necrotizing pulmonary aspergillosis in a patient treated with a tumor necrosis factor-, inhibitorINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2010Eun Jung LEE Abstract Tumor necrosis factor (TNF)-, is a pro-inflammatory cytokine that plays an important role in the pathogenesis of a variety of autoimmune diseases. TNF-, inhibitors have been shown to offer clinical benefits in the treatment of autoimmune and inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis (AS), and Crohn's disease. Occasionally, these agents have been associated with infectious complications because of their immunosuppressive activity. Globally, several cases of infections associated with TNF-, inhibitors have been reported. However, Aspergillus infection associated with etanercept is very rare. We report a case of chronic necrotizing pulmonary aspergillosis in a 51-year-old man with AS that developed after treatment with etanercept. [source] Clinical experience with tumor necrosis factor blockers in Korean rheumatoid arthritis patientsINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2 2006Jin-Wuk HUR Abstract Tumor necrosis factor (TNF) blockers have become an important treatment in rheumatoid arthritis (RA) with its proven effectiveness. But it is not universally effective in all patients and it comes with a relatively high economic burden. We should use them effectively. Advances in pharmacoeconomics and pharmacogenetics may be able to help us reach this goal. This article will review our clinical experience of biological agents to treat RA at Hanyang University in Korea, with emphasis on the current therapies targeting TNF and the rational use of theses agents in RA. [source] Effects of surfactant replacement on alveolar overdistension and plasma cytokines in ventilator-induced lung injuryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2010H. WU Background: Overdistension of the lung causes ventilator-induced lung injury (VILI) accompanied by surfactant abnormalities and inflammatory changes. We investigated the effects of surfactant replacement on overdistension of the terminal airspaces and plasma cytokine levels in VILI. Methods: VILI was induced by high-pressure ventilation (HPV) in rats anesthetized with pentobarbital, followed by ventilation for 2 h in the maintenance mode (tidal volume=10 ml/kg, positive end-expiratory pressure=7.5 cmH2O) with or without surfactant replacement. The sizes of the terminal airspaces were determined after fixing the lungs at an airway pressure of 10 cmH2O on deflation. Cytokine levels were assessed by enzyme-linked immunosorbent assay. Results: The mean ratio of the largest terminal airspace size class (,64,000 ,m2) was increased from 13.4% to 32.0% by HPV (P<0.05). After maintenance-mode ventilation, the ratio decreased to 16.1% with surfactant replacement (P<0.05), but increased to 44.6% without surfactant replacement (P<0.05). Mean macrophage inflammatory protein-2 (MIP-2) levels in the plasma increased from <0.02 to 6.9 ng/ml with HPV (P<0.05), and further increased to ,11.8 ng/ml, regardless of surfactant replacement after maintenance-mode ventilation. Similar tendencies were observed in the interleukin (IL)-6 and IL-10 levels. Tumor necrosis factor-, levels were almost negligible during the experiment. Conclusion: In rats with VILI, surfactant replacement reversed overdistension of the terminal airspaces that may induce barotrauma, but not upregulation of MIP-2, IL-6, and IL-10 within 2 h. [source] Propofol has anti-inflammatory effects on alveolar type II epithelial cellsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2010L. MA Background: We investigated whether lipopolysaccharide (LPS) induced inflammation in alveolar epithelial type II (ATII) cells is through cluster of differentiation 14 (CD14) and Toll-like receptor 4 (TLR4) and the effect of different dosages of propofol on the inflammation in primary cultured rat ATII cells. Methods: Cultured ATII cells were randomly assigned to one of the following five groups: Group C: untreated group (control) cultured in the absence of propofol and LPS; Group LPS: treated with 1 ,g/ml LPS; Group P1: treated with 1 ,g/ml LPS and 25 ,M propofol; Group P2: treated with 1 ,g/ml LPS and 50 ,M propofol; Group P3: treated with 1 ,g/ml LPS and 100 ,M propofol. ATII cells in all groups were cultured at 37 °C for 3 h. CD14 and TLR4 mRNA was detected using real-time polymerase chain reaction. Western blot was used to detect CD14 and TLR4 protein expression. CD14 and TLR4 expression on the ATII cells was imaged using immunofluorescence. Tumor necrosis factor-, (TNF-,) production was determined using an ELISA kit. Results: LPS stimulation resulted in an increased CD14 and TLR4 expression and increased TNF-, production in ATII cells. Propofol, at concentrations ,50 ,M, significantly (P<0.05) and dose-dependently decreased CD14 and TLR4 mRNA expression and protein expression in ATII cells. This was accompanied by a decrease in TNF-, production (P<0.05). Conclusion: These results suggest that propofol, at clinically relevant concentrations, can reduce inflammatory responses in LPS-induced ATII cells injury through downregulation of CD14 and TLR4 expression. [source] Variation in the TNF Gene Promoter and Risk of Osteolysis After Total Hip ArthroplastyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2003FRCS, J Mark Wilkinson PhD Abstract Genetic factors may influence implant failure caused by osteolysis after THA. In an association study of 481 subjects after THA, we found that carriage of the TNF - 238A allele was associated with an increased incidence of osteolysis versus noncarriage (odds ratio, 1.7) and was independent of other risk factors. Genetic and environmental factors influence implant survival after THA. Introduction: Tumor necrosis factor (TNF) is thought to play a role in osteolysis, the major cause of implant failure after total hip arthroplasty (THA). Natural sequence variations at ,238 and ,308 in the TNF gene promoter are associated with differences in susceptibility to several TNF-mediated diseases. We tested whether these polymorphisms are associated with osteolysis after THA. Materials and Methods: A total of 481 whites (214 with failed versus 267 with intact implants) were recruited 11.7 ± 4 years after cemented THA. Genomic DNA was extracted from peripheral blood and genotyped for the ,238 and ,308 polymorphisms using the Taqman 5, nuclease method. Healthy controls (n = 500) from the background population were also genotyped to establish the local prevalence of these alleles. Results: The carriage of ,238A was 8.8% in the background population and 10.9% in the THA controls (p > 0.05). Carriage of ,238A in the osteolysis group was 17.3% (odds ratio, 1.7; 95% CI, 1.0,2.9). Carriage was highest (20.5%) in patients with more widespread osteolysis (OR, 2.1; 1.2,3.8). The association of ,238A with osteolysis was independent of other risk factors for osteolysis (logistic regression analysis: OR, 1.8; 1.0,3.2). Carriage of ,308A was not associated with osteolysis. Conclusion: Genetic, as well as environmental factors, influence implant failure after THA. Whether the TNF - 238 polymorphism causes a biological change that predisposes to loosening or is in linkage disequilibrium with such a locus is not yet known. [source] | |||||||||||||||||||||||||||||||||||||||||||