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1

Tumor Necrosis factor-alpha Induces Adhesion Molecule Expression through the Sphingosine Kinase Pathway  

Microsoft Academic Search

The signaling pathways that couple tumor necrosis factor-alpha (TNFalpha ) receptors to functional, especially inflammatory, responses have remained elusive. We report here that TNFalpha induces endothelial cell activation, as measured by the expression of adhesion protein E-selectin and vascular adhesion molecule-1, through the sphingosine kinase (SKase) signaling pathway. Treatment of human umbilical vein endothelial cells with TNFalpha resulted in a

Pu Xia; Jennifer R. Gamble; Kerry-Anne Rye; Lijun Wang; Charles S. T. Hii; Peter Cockerill; Yeesim Khew-Goodall; Andrew G. Bert; Philip J. Barter; Mathew A. Vadas

1998-01-01

2

Arsenite enhances tumor necrosis factor-{alpha}-induced expression of vascular cell adhesion molecule-1  

SciTech Connect

Epidemiological studies demonstrated a high association of vascular diseases with arsenite exposure. We hypothesize that arsenite potentiates the effect of proinflammatory cytokines on vascular endothelial cells, and hence contributes to atherosclerosis. In this study, we investigated the effect of arsenite and its induction of glutathione (GSH) on vascular cell adhesion molecule-1 (VCAM-1) protein expression in human umbilical vein endothelial cells (HUVECs) in response to tumor necrosis factor-{alpha} (TNF-{alpha}), a typical proinflammatory cytokine. Our study demonstrated that arsenite pretreatment potentiated the TNF-{alpha}-induced VCAM-1 expression with up-regulations of both activator protein-1 (AP-1) and nuclear factor-{kappa}B (NF-{kappa}B). To elucidate the role of GSH in regulation of AP-1, NF-{kappa}B, and VCAM-1 expression, we employed L-buthionine (S,R)-sulfoximine (BSO), a specific {gamma}-glutamylcysteine synthetase ({gamma}-GCS) inhibitor, to block intracellular GSH synthesis. Our investigation revealed that, by depleting GSH, arsenite attenuated the TNF-{alpha}-induced VCAM-1 expression as well as a potentiation of AP-1 and an attenuation of NF-{kappa}B activations by TNF-{alpha}. Moreover, we found that depletion of GSH would also attenuate the TNF-{alpha}-induced VCAM-1 expression with a down-regulation of the TNF-{alpha}-induced NF-{kappa}B activation and without significant effect on AP-1. On the other hand, the TNF-{alpha}-induced VCAM-1 expression could be completely abolished by inhibition of AP-1 or NF-{kappa}B activity, suggesting that activation of both AP-1 and NF-{kappa}B was necessary for VCAM-1 expression. In summary, we demonstrate that arsenite enhances the TNF-{alpha}-induced VCAM-1 expression in HUVECs via regulation of AP-1 and NF-{kappa}B activities in a GSH-sensitive manner. Our present study suggested a potential mechanism for arsenite in the induction of vascular inflammation and vascular diseases via modulating the actions of proinflammatory cytokines.

Tsou, T.-C. [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan (China)]. E-mail: tctsou@nhri.org.tw; Yeh, Szu Ching [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan (China); Tsai, E.-M. [Department of Obstetrics and Gynecology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Department of Obstetrics and Gynecology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan (China); Tsai, F.-Y. [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan (China); Chao, H.-R. [Department of Environmental and Safety Health Engineering, Chung Hwa College of Medical Technology, Tainan, Taiwan (China); Chang, Louis W. [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan (China)

2005-11-15

3

Expression of transforming growth factor alpha in plutonium-239-induced lung neoplasms in dogs: investigations of autocrine mechanisms of growth  

SciTech Connect

We have previously shown that 47% of radiation-induced lung neoplasms in dogs exhibit increased expression of epidermal growth factor receptor (EGFR). In this study, we investigated the expression of transforming growth factor alpha (TGF-alpha), a ligand for EGFR, to determine if an autocrine mechanism for growth stimulation was present in these tumors. As determined by immunohistochemistry, 59% (26/44) of the lung neoplasms examined had increased expression of TGF-alpha. Expression of TGF-alpha was not related to the etiology of the tumor, e.g., spontaneous or plutonium-induced; however, it was related to the phenotype of the tumor. Statistical analysis of the correlation of EGFR and TGF-alpha expression within the same tumor did not show a positive association; however, specific phenotypes did have statistically significant expression of EGFR or TGF-alpha, suggesting that overexpression of either the ligand or its receptor conferred a growth advantage to the neoplasm. Twenty-seven percent (32/117) of radiation-induced proliferative epithelial foci expressed TGF-alpha, and a portion of those foci (8/32) expressed both EGFR and TGF-alpha. This supports the hypothesis that these foci represent preneoplastic lesions, and suggests that those foci exhibiting increased expression of the growth factor or its receptor are at greater risk for progressing to neoplasia.

Gillett, N.A.; Stegelmeier, B.L.; Chang, I.Y.; Kelly, G. (Lovelace Biomedical and Environmental Research Institute, Albuquerque, NM (USA))

1991-06-01

4

Expression of transforming growth factor alpha and epidermal growth factor receptor in rat lung neoplasms induced by plutonium-239  

SciTech Connect

Ninety-two rat lung proliferative lesions and neoplasms induced by inhaled {sup 239}PuO{sub 2} were evaluated for aberrant expression of transforming growth factor alpha (TGF-{alpha}) and epidermal growth factor receptor (EGFR). Expression of TGF-{alpha} protein, measured by immunohistochemistry, was higher in 94% of the squamous cell carcinomas and 87% of the foci of alveolar epithelial squamous metaplasia than that exhibited by the normal-appearing, adjacent lung parenchyma. In contrast, only 20% of adenocarcinomas and foci of epithelial hyperplasia expressed elevated levels of TGF-{alpha}. Many neoplasms expressing TGF-{alpha} also expressed excessive levels of EGFR mRNA. Southern and DNA slot blot analyses showed that the elevated EGFR expression was not due to amplification of the EGFR gene. These data suggest that increased amounts of TGF-{alpha} were early alterations in the progression of plutonium-induced squamous cell carcinoma, and these increases may occur in parallel with overexpression of the receptor for this growth factor. Together, these alterations create a potential autocrine loop for sustaining clonal expansion of cells initiated by high-LET radiation. 44 refs., 4 figs., 1 tab.

Stegelmeier, B.L.; Gillett, N.A.; Hahn, F.F.; Kelly, G. [Inhalation Toxicology Research Institute, Albuquerque, NM (United States); Rebar, A.H. [Purdue Univ., West Lafayette, IN (United States)

1994-11-01

5

UV-DNA damage in mouse and human cells induces the expression of tumor necrosis factor alpha.  

PubMed

Ultraviolet light induces the expression of tumor necrosis factor alpha (TNF alpha) in many mammalian cells. We have examined the signal for this induction in a human DNA repair-deficient cell line carrying a transgene composed of the murine TNF regulatory sequences fused to the chloramphenicol acetyltransferase (CAT) structural gene. When compared by fluence, UVC was a more efficient inducer of CAT than was UVB, but they were equivalent inducers when compared by the frequency of cyclobutyl pyrimidine dimers produced by each source. Further, treatment of UV-irradiated cells with the prokaryotic DNA repair enzyme T4 endonuclease V increased the level of repair of dimers and concomitantly reduced CAT gene expression. Membrane-bound TNF alpha expression was increased by UV and reduced by repair of dimers. Finally, in the TNFcat transgene system, DNA damage directly to the cell with the transgene was required as cocultivation of unirradiated TNFcat cells with UV-irradiated cells did not increase CAT activity. These results show that DNA damage is a signal for the induction of TNF alpha gene expression in mouse and human cells. PMID:9644008

Kibitel, J; Hejmadi, V; Alas, L; O'Connor, A; Sutherland, B M; Yarosh, D

1998-05-01

6

Pertussis toxin-induced hyperacute autoimmune encephalomyelitis in Lewis rats is correlated with increased expression of inducible nitric oxide synthase and tumor necrosis factor alpha  

Microsoft Academic Search

The involvement of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-?), which have diverse roles in the progression of autoimmune disease models, was studied in pertussis toxin (PT)-induced hyperacute experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The expression of TNF-? mRNA (increased 5-fold, P<0.01) and iNOS protein (3-fold, P<0.01) was much greater in the spinal cords with

Meejung Ahn; Jongchul Kang; Yongduk Lee; Keyzung Riu; Yong-sik Kim; Youngheun Jee; Yoh Matsumoto; Taekyun Shin

2001-01-01

7

Ginsenoside Rg3 inhibits tumor necrosis factor-alpha-induced expression of cell adhesion molecules in human endothelial cells.  

PubMed

Ginsenoside Rg3 (Rg3), one of the most effective ginseng saponins, has anti-inflammatory and anti-cancer effects. This study examined the effects of Rg3 on cytokine-induced expression of adhesion molecules, which is a key early event in atherogenesis. Rg3 treatment inhibited tumor necrosis factor-alpha (TNF-alpha)-induced protein and mRNA expression of two cell adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) in ECV 304 human endothelial cells. In addition, expression of two pro-inflammatory cytokines, TNF-alpha and interleukin-1beta (IL-1beta), was suppressed by Rg3. Reporter gene analyses revealed that minimal reporter activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were blocked by Rg3 in a concentration-dependent manner. Taken together, these results indicate that Rg3 may have anti-inflammatory and anti-atherosclerotic activities in the vasculature, which is mediated partly by down-regulation of the expression of cell adhesion molecules and proinflammatory cytokines in endothelial cells. PMID:21038849

Hien, Tran Thi; Kim, Nak Doo; Kim, Hyung Sik; Kang, Keon Wook

2010-09-01

8

Tumor necrosis factor alpha induces the expression of transforming growth factor alpha and the epidermal growth factor receptor in human pancreatic cancer cells.  

PubMed Central

Recombinant human tumor necrosis factor (TNF)-alpha increased the expression of epidermal growth factor receptor (EGFR) mRNA and protein in all of six human pancreatic carcinoma cell lines tested. In addition, TNF-alpha increased the expression of an EGFR ligand, transforming growth factor (TGF)-alpha, at the mRNA and protein level in all cell lines. Increased expression of EGFR protein was associated with elevated steady-state EGFR mRNA levels. Nuclear run-on analysis showed that increase in EGFR mRNA was due to an increased rate of transcription. Induction of EGFR mRNA expression by TNF-alpha was abrogated by cycloheximide but occurred independently of TNF-alpha-induced production of TGF-alpha protein. Protein kinase A or Gi-type guanine nucleotide-binding proteins were not involved in this process as assessed by using appropriate stimulators and inhibitors of these signal transduction pathways. By contrast, staurosporine, an inhibitor of protein kinase C, partially inhibited, and 4-bromophenacyl bromide, a phospholipase inhibitor, completely inhibited TNF-alpha-dependent EGFR mRNA expression. The phospholipase C-specific inhibitor tricyclodecan-9-yl xanthogenate did not alter TNF-alpha-dependent EGFR mRNA expression, suggesting that phospholipase A2 is involved in the modulation of EGFR expression by TNF-alpha. The simultaneous induction of a ligand/receptor system by TNF-alpha suggests that this cytokine modulates autocrine growth-regulatory pathways in pancreatic cancer cells. Images

Schmiegel, W; Roeder, C; Schmielau, J; Rodeck, U; Kalthoff, H

1993-01-01

9

Tumor necrosis factor alpha induces gamma-glutamyltransferase expression via nuclear factor-kappaB in cooperation with Sp1.  

PubMed

Gamma-glutamyltransferase (GGT) cleaves the gamma-glutamyl moiety of glutathione (GSH), an endogenous antioxidant, and is involved in mercapturic acid metabolism and in cancer drug resistance when overexpressed. Moreover, GGT converts leukotriene (LT) C4 into LTD4 implicated in various inflammatory pathologies. So far the effect of inflammatory stimuli on regulation of GGT expression and activity remained to be addressed. We found that the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) induced GGT promoter transactivation, mRNA and protein synthesis, as well as enzymatic activity. Remicade, a clinically used anti-TNFalpha antibody, small interfering RNA (siRNA) against p50 and p65 nuclear factor-kappaB (NF-kappaB) isoforms, curcumin, a well characterized natural NF-kappaB inhibitor, as well as a dominant negative inhibitor of kappaB alpha (IkappaBalpha), prevented GGT activation at various levels, illustrating the involvement of this signaling pathway in TNFalpha-induced stimulation. Over-expression of receptor of TNFalpha-1 (TNFR1), TNFR-associated factor-2 (TRAF2), TNFR-1 associated death domain (TRADD), dominant negative (DN) IkappaBalpha or NF-kappaB p65 further confirmed GGT promoter activation via NF-kappaB. Linker insertion mutagenesis of 536 bp of the proximal GGT promoter revealed NF-kappaB and Sp1 binding sites at -110 and -78 relative to the transcription start site, responsible for basal GGT transcription. Mutation of the NF-kappaB site located at -110 additionally inhibited TNFalpha-induced promoter induction. Chromatin immunoprecipitation (ChIP) assays confirmed mutagenesis results and further demonstrated that TNFalpha treatment induced in vivo binding of both NF-kappaB and Sp1, explaining increased GGT expression, and led to RNA polymerase II recruitment under inflammatory conditions. PMID:18996094

Reuter, Simone; Schnekenburger, Michael; Cristofanon, Silvia; Buck, Isabelle; Teiten, Marie-Hélène; Daubeuf, Sandrine; Eifes, Serge; Dicato, Mario; Aggarwal, Bharat B; Visvikis, Athanase; Diederich, Marc

2008-10-18

10

Reduction of Tumor Necrosis Factor Alpha-Inducing Capacity of Recombinant Lactobacillus casei via Expression of Salmonella OmpC?  

PubMed Central

The insertion of a heterologous gene into commensal bacteria is a common technique to develop a delivery agent for vaccination and therapies, but the pleiotropic effects of genetic modifications need to be investigated before its use in practical applications. Although supplemental properties provided by the expression of heterologous antigens have been reported, the negative or side effects on the immune-modulating properties caused by recombination are barely understood. In the present study, we fortuitously found that the secretion of tumor necrosis factor alpha (TNF-?) from murine macrophages was reduced by recombinant Lactobacillus casei expressing Salmonella OmpC compared to the stimulation of TNF-? secretion by nonexpressing L. casei. This reduction could not be attributed to OmpC as a purified protein. The main component of the OmpC-expressing strain included in the attenuation of TNF-? release seemed to be the cell wall, which exhibited higher sensitivity against N-acetylmuramidase than that of nonexpressing strains. These results suggest that the recombinant strain expressing a specific heterologous antigen might be digested rapidly in macrophages and lose immune-stimulating capability at an early time point.

Kajikawa, A.; Igimi, S.

2009-01-01

11

Regulation of tumor necrosis factor alpha- and interleukin-1-beta-induced induced adhesion molecule expression in human vascular smooth muscle cells by cAMP.  

PubMed

This study investigates the hypothesis that the elevation of intracellular cAMP may affect cytokine-induced expression of adhesion molecules on human vascular smooth muscle cells. In cultured human smooth muscle cells from coronary arteries and saphenous veins, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) induced the expression of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1), whereas interferon-gamma (INF-gamma) selectively stimulated the expression of ICAM-1. Adenylyl cyclase was stimulated either by the stable prostacyclin mimetic cicaprost or by forskolin. Adhesion molecules were detected by a cell surface enzyme immunoassay and the respective mRNA by reverse transcriptase polymerase chain reaction (rt-PCR). Cicaprost as well as forskolin significantly inhibited TNF-alpha- and IL-1 beta-induced cell surface expression of ICAM-1 and VCAM-1. Semiquantitative rt-PCR measurements showed a marked decrease of TNF-alpha- and IL-1 beta-induced mRNA levels of both adhesion molecules after preincubation with cicaprost. The stability of TNF-alpha-induced ICAM-1 and VCAM-1 expression at mRNA and protein level was not altered by cicaprost. The IFN-gamma-induced increase of cell surface expression of ICAM-1 and the respective mRNA levels, however, were not significantly altered by elevation of intracellular cAMP. Basal and stimulated cAMP levels, measured by radioimmunoassay, did not differ in TNF-alpha- and IFN gamma-treated cells. The present results demonstrate that the expression of adhesion molecules on human smooth muscle cells induced by cytokines is differentially modulated by activation of adenylyl cyclase. PMID:9409229

Braun, M; Pietsch, P; Zepp, A; Schrör, K; Baumann, G; Felix, S B

1997-11-01

12

Pertussis toxin-induced hyperacute autoimmune encephalomyelitis in Lewis rats is correlated with increased expression of inducible nitric oxide synthase and tumor necrosis factor alpha.  

PubMed

The involvement of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-alpha), which have diverse roles in the progression of autoimmune disease models, was studied in pertussis toxin (PT)-induced hyperacute experimental autoimmune encephalomyelitis (EAE) in Lewis rats. The expression of TNF-alpha mRNA (increased 5-fold, P<0.01) and iNOS protein (3-fold, P<0.01) was much greater in the spinal cords with PT(+) EAE at the peak stage of EAE than in those with PT(-) EAE, as shown by competitive PCR and Western blot analysis, respectively. Immunohistochemistry showed that the majority of ED1-positive macrophages in EAE lesions contained iNOS, and that there were many more iNOS-positive cells in the CNS lesions of PT(+) rats than in those of PT(-) rats. These findings suggest that PT-induced hyperacute EAE is partly mediated by the enhanced expression of iNOS and TNF-alpha in the early stages of rat EAE. PMID:11445281

Ahn, M; Kang, J; Lee, Y; Riu, K; Kim, Y; Jee, Y; Matsumoto, Y; Shin, T

2001-07-27

13

HIV-1 transgene expression in rats induces differential expression of tumor necrosis factor alpha and zinc transporters in the liver and the lung  

PubMed Central

Background Highly effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1-related viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging. HIV-1 transgenic rodent models are useful for studying the systemic effects of these proteins independently of viral infection. We have previously shown that HIV-1 transgene expression (and therefore, HIV-1-related protein expression) in rats decreases alveolar macrophage zinc levels and phagocytic capacity by unknown mechanisms. We hypothesized that HIV-1 transgene expression induces chronic inflammation and zinc sequestration within the liver and thereby decreases zinc bioavailability in the lung. We examined the expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF?), the zinc storage protein, metallothionein (MT1), and the zinc exporter, ZNT1 in the livers and the lungs of wild type and HIV-1 transgenic rats ± dietary zinc supplementation. In addition, we measured zinc levels, the zinc importing protein ZIP1, and the phagocytic capacity in the alveolar macrophages. Results HIV-1 transgene expression increased the liver-specific expression of TNF?, suggesting a chronic inflammatory response within the liver in response to HIV-1-related protein expression. In parallel, HIV-1 transgene expression significantly increased MT1 and ZNT1 expression in the liver as compared to the lung, a pattern that is consistent with zinc sequestration in the liver as occurs during systemic inflammation. Further, HIV-1 transgene expression decreased intracellular zinc levels and increased expression of ZIP1 in the alveolar macrophages, a pattern consistent with zinc deficiency, and decreased their bacterial phagocytic capacity. Interestingly, dietary zinc supplementation in HIV-1 transgenic rats decreased gene expression of TNF?, MT1, and ZNT1 in the liver while simultaneously increasing their expression in the lung. In parallel, zinc supplementation increased alveolar macrophage intracellular zinc levels and bacterial phagocytic capacity in HIV-1 transgenic rats. Conclusion Taken together, these findings suggest that chronic HIV-1-related protein expression causes liver inflammation and zinc sequestration, which in turn limits zinc bioavailability in the lung and thereby impairs alveolar macrophage phagocytic function. Importantly, dietary zinc supplementation decreases liver inflammation and zinc sequestration and restores alveolar macrophage phagocytic function in HIV-1 transgenic rats, a result with potential clinical implications for improving lung health in HIV-1-infected individuals.

2011-01-01

14

Resistance to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in rat hepatoma cells expressing TNF-alpha is linked to low antioxidant enzyme expression.  

PubMed

In order to study the mechanisms of resistance to tumor necrosis factor-alpha (TNF-alpha), we have constructed two stable transfectants producing TNF-alpha (Yv12-2 and Yv13-44) from the rat hepatoma H4IIE cell, which does not produce TNF-alpha. H4IIE cells were highly sensitive to apoptosis induced by TNF-alpha, whereas Yv2-12 and Yv13-44 cells were resistant. Manganous superoxide dismutase was not up-regulated in Yv2-12 and Yv13-44 cells and was unresponsive to induction by exogenous TNF-alpha and by H2O2 in H4IIE cells and in the transfectants. Catalase expression and activity were lower in Yv2-12 and Yv13-44 cells than in H4IIE cells; furthermore, the transfectants were more susceptible to H2O2. Treatment with exogenous TNF-alpha down-regulated catalase in H4IIE cells but not in Yv2-12 and Yv13-44 cells. Treatment of H4IIE cells with the catalase inhibitor 3-amino-1,2,4-triazole rendered them resistant to exogenous TNF-alpha. These data suggest a causal relationship between resistance to TNF-alpha and low catalase activity. Expression of copper and zinc containing superoxide dismutase was also decreased, whereas expression of glutathione peroxidase-1 was unchanged in Yv2-12 and Yv13-44 cells. Data from a microarray point to a down-regulation of genes in the resistant clones that code for antioxidative proteins and proteins involved in glutathione synthesis and function. We assume that a prooxidant signal linked to the down-regulation of antioxidant defense may be associated with resistance to apoptosis induced by TNF-alpha. PMID:12775721

Chovolou, Yvonni; Watjen, Wim; Kampkotter, Andreas; Kahl, Regine

2003-05-29

15

The coffee diterpene kahweol inhibits tumor necrosis factor-{alpha}-induced expression of cell adhesion molecules in human endothelial cells  

SciTech Connect

Endothelial cells produce adhesion molecules after being stimulated with various inflammatory cytokines. These adhesion molecules play an important role in the development of atherogenesis. Recent studies have highlighted the chemoprotective and anti-inflammatory effects of kahweol, a coffee-specific diterpene. This study examined the effects of kahweol on the cytokine-induced monocyte/human endothelial cell interaction, which is a crucial early event in atherogenesis. Kahweol inhibited the adhesion of TNF{alpha}-induced monocytes to endothelial cells and suppressed the TNF{alpha}-induced protein and mRNA expression of the cell adhesion molecules, VCAM-1 and ICAM-1. Furthermore, kahweol inhibited the TNF{alpha}-induced JAK2-PI3K/Akt-NF-{kappa}B activation pathway in these cells. Overall, kahweol has anti-inflammatory and anti-atherosclerotic activities, which occurs partly by down-regulating the pathway that affects the expression and interaction of the cell adhesion molecules on endothelial cells.

Kim, Hyung Gyun [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of); Kim, Ji Young [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of); Hwang, Yong Pil [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of); Lee, Kyung Jin [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of); Lee, Kwang Youl [Department of Pharmacy, College of Pharmacy, Chonnam National University, Kwangju (Korea, Republic of); Kim, Dong Hee [Department of Pathology, College of Oriental Medicine, Daejeon University, Daejeon (Korea, Republic of); Kim, Dong Hyun [Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul (Korea, Republic of); Jeong, Hye Gwang [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of)]. E-mail: hgjeong@chosun.ac.kr

2006-12-15

16

Tumor necrosis factor-alpha regulates inducible nitric oxide synthase gene expression in the portal hypertensive gastric mucosa of the rat.  

PubMed

Increased expression of both nitric oxide synthase (NOS) and tumor necrosis factor-alpha (TNF-alpha) have been implicated in the hyperdynamic circulation of portal hypertension. Since overexpression of these proteins would affect gastric mucosal defenses, which are impaired in portal hypertension, we examined the expression and interrelationships of TNF-alpha and NOS in the gastric mucosa of portal hypertensive rats. Following staged portal vein ligation, gastric strips from portal hypertensive rats were incubated in organ culture medium with or without TNF-alpha antibody. The expression of TNF-alpha and NOS mRNAs was assessed by reverse transcription-polymerase chain reaction (RT-PCR) at baseline and after 1, 2, and 6 hours of incubation. RT-PCR demonstrated a threefold increase in inducible NOS mRNA and a 50% increase in TNF-alpha mRNA expression at baseline in portal hypertensive animals as compared to sham-operated animals. In tissue incubated with TNF-alpha neutralizing antibody, inducible NOS mRNA expression was significantly decreased by 40%, 70%, and 80% after 1, 2, and 6 hours, respectively. Since increased TNF-alpha and NOS production could potentially impair gastric mucosal defenses, our findings suggest a major role for these proteins in the development of portal hypertensive gastropathy. PMID:9834372

Kaviani, A; Ohta, M; Itani, R; Sander, F; Tarnawski, A S; Sarfeh, I J

17

Increased gene expression of novel cytosolic and secretory phospholipase A(2) types in human airway epithelial cells induced by tumor necrosis factor-alpha and IFN-gamma.  

PubMed

Phospholipase A(2) (PLA(2)) is a growing family of enzymes that may play a major role in inflammation. We investigated the effect of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on the gene expression of 19 different PLA(2) types (IB, IIA, IID, IIE, IIF, III, IVA, IVB, IVC, V, VIA, VIB, VIIA, VIIB, VIIIA, VIIIB, X, XII, and XIII) in human bronchoepithelial (BEAS-2B) and nasal epithelial (RPMI 2650) cells. The cells were stimulated with TNF-alpha or IFN-gamma for different lengths of time (1, 4, 18, and 48 h), and the mRNA levels of the different PLA(2) types were determined by reverse transcriptase-PCR (RT-PCR) and normalized to those of the housekeeping gene, GAPDH. In both cell lines, TNF-alpha increased the expression of PLA(2) IVA and IVC, and IFN-gamma increased the expression of PLA(2) IIA and IID. No influence on the gene expression of PLA(2)-activating protein (PLAP) was noted on cytokine stimulation. These findings indicate that TNF-alpha and IFN-gamma induce gene expression of two novel cytosolic and secretory PLA(2) types (IVC and IID, respectively) in human airway epithelial cells. The possibility that these PLA(2) types are involved in cytokine-mediated inflammation in the respiratory tract is inferred. PMID:12396716

Lindbom, John; Ljungman, Anders G; Lindahl, Mats; Tagesson, Christer

2002-09-01

18

Extract of corn silk (stigma of Zea mays) inhibits the tumour necrosis factor-alpha- and bacterial lipopolysaccharide-induced cell adhesion and ICAM-1 expression.  

PubMed

Treatment of human endothelial cells with cytokines such as tumour necrosis factor-alpha (TNF) or E. coli lipopolysaccharide (LPS) induces the expression of several adhesion molecules and enhances leukocyte adhesion to endothelial cell surface. Interfering with this leukocyte adhesion or adhesion molecules upregulation is an important therapeutic target for the treatment of bacterial sepsis and various inflammatory diseases. In the course of screening marketed European anti-inflammatory herbal drugs for TNF antagonistic activity, a crude ethanolic extract of corn silk (stigma of Zea mays) exhibited significant activity. The extract at concentrations of 9-250 micrograms/ml effectively inhibited the TNF- and LPS-induced adhesiveness of EAhy 926 endothelial cells to monocytic U937 cells. Similar concentration ranges of corn silk extract did also block the TNF and LPS but not the phorbol 12-myristate 13-acetate-induced ICAM-1 expression on EAhy 926 endothelial cell surface. The extract did not alter the production of TNF by LPS-activated macrophages and failed to inhibit the cytotoxic activity of TNF. It is concluded that corn silk possesses important therapeutic potential for TNF- and LPS-mediated leukocyte adhesion and trafficking. PMID:9619111

Habtemariam, S

1998-05-01

19

Specific NF-kappaB blockade selectively inhibits tumour necrosis factor-alpha-induced COX-2 but not constitutive COX-1 gene expression in HT-29 cells.  

PubMed Central

Cyclo-oxygenase (COX) is the key regulatory enzyme of the prostaglandin/eicosanoid pathway. While COX-1 is mostly constitutively expressed, the COX-2 isoform is inducible by proinflammatory cytokines. We used an adenoviral vector containing an NF-kappaB super-repressor (Ad5IkappaB) to investigate the role of NF-kappaB in tumour necrosis factor-alpha (TNF-alpha)-mediated COX-2 gene expression in a colonic epithelial cell line. COX-1 mRNA and protein were constitutively expressed in uninfected, control Ad5LacZ- or Ad5IkappaB-infected HT-29 cells with no apparent change following TNF-alpha exposure. COX-2 mRNA and protein expression was undetectable in unstimulated cells but was strongly up-regulated after TNF-alpha stimulation in uninfected and Ad5LacZ-infected HT-29 cells. This induction was prevented in Ad5IkappaB cells. TNF-alpha increased prostaglandin E2 production by 20-fold in Ad5LacZ-infected HT-29 cells compared with uninfected cells and was significantly inhibited in Ad5IkappaB-infected cells in agreement with the COX-2 mRNA findings. We conclude that NF-kappaB activation is critical in mediating COX-2, but not COX-1 gene expression in HT-29 cells. Selective inhibition of COX-2 expression with the NF-kappaB super-repressor may be useful in distinguishing the role of inducible versus constitutive prostaglandins in intestinal function and provides greater specificity than pharmacological inhibitors. Images Figure 1 Figure 2 Figure 3

Jobin, C; Morteau, O; Han, D S; Balfour Sartor, R

1998-01-01

20

Expression of Tumor Necrosis Factor Alpha-Induced Protein 3 mRNA in Peripheral Blood Mononuclear Cells Negatively Correlates with Disease Severity in Psoriasis Vulgaris  

PubMed Central

Psoriasis vulgaris is considered a chronic inflammatory disease, but its immunopathogenesis has not been well understood. The tumor necrosis factor alpha-induced protein 3 (TNFAIP3) gene functions in negative-feedback regulation of inflammation, and its single nucleotide polymorphism is associated with psoriasis. However, the relationship between the expression level of the TNFAIP3 gene in immune cells and psoriasis is not known so far. In the present study, TNFAIP3 mRNA expression levels in peripheral blood mononuclear cells from 44 patients with psoriasis vulgaris and 30 healthy controls were determined using real-time reverse transcription-PCR analysis. We found that expression of TNFAIP3 mRNA in all patients negatively correlated with the psoriatic area and severity index (PASI) (r = ?0.5126; P = 0.0004) as well as with the percentage of body surface area affected by psoriasis (r = ?0.5013; P = 0.0005). Patients were divided into mild and severe groups based on the mean PASI score. Expression of TNFAIP3 mRNA in the mild group was higher than that in the severe group (P = 0.0064). Moreover, compared with that in healthy controls, the expression of TNFAIP3 mRNA in the mild group was significantly upregulated (P = 0.0004), but the expression of TNFAIP3 mRNA in the severe group was not. These results suggest that the expression level of TNFAIP3 plays an important role in the pathology of psoriasis vulgaris and that the loss of upregulation of TNFAIP3 expression may contribute to the severity of psoriasis vulgaris.

Jiang, Xuebing; Tian, Hongqing; Fan, Yuchen; Chen, Jie; Song, Yonghong; Wang, Shurong; Zhu, Faliang; Guo, Chun; Zhang, Lining

2012-01-01

21

Tumor necrosis factor-alpha regulates inducible nitric oxide synthase gene expression in the portal hypertensive gastric mucosa of the rat  

Microsoft Academic Search

Increased expression of both nitric oxide synthase (NOS) and tumor necrosis factor-alpha (TNF-?) have been implicated in the\\u000a hyperdynamic circulation of portal hypertension. Since overexpression of these proteins would affect gastric mucosal defenses,\\u000a which are impaired in portal hypertension, we examined the expression and interrelationships of TNF-? and NOS in the gastric\\u000a mucosa of portal hypertensive rats. Following staged portal

Amir Kaviani; Masayuki Ohta; Rabiha Itani; Fred Sander; Andrzej S. Tarnawski; I. James Sarfeh

1997-01-01

22

Reduction of Tumor Necrosis Factor Alpha-Inducing Capacity of Recombinant Lactobacillus casei via Expression of Salmonella OmpC  

Microsoft Academic Search

The insertion of a heterologous gene into commensal bacteria is a common technique to develop a delivery agent for vaccination and therapies, but the pleiotropic effects of genetic modifications need to be investigated before its use in practical applications. Although supplemental properties provided by the expression of heterologous antigens have been reported, the negative or side effects on the immune-modulating

A. Kajikawa; S. Igimi

2009-01-01

23

Tumor necrosis factor-{alpha} induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-{kappa}B in A549 cells  

SciTech Connect

Matrix metalloproteinases (MMPs), in particular MMP-9, have been shown to be induced by cytokines including tumor necrosis factor-{alpha} (TNF-{alpha}) and contributes to airway inflammation. However, the mechanisms underlying MMP-9 expression induced by TNF-{alpha} in human A549 cells remain unclear. Here, we showed that TNF-{alpha} induced production of MMP-9 protein and mRNA is determined by zymographic, Western blotting, RT-PCR and ELISA assay, which were attenuated by inhibitors of MEK1/2 (U0126), JNK (SP600125), and NF-{kappa}B (helenalin), and transfection with dominant negative mutants of ERK2 ({delta}ERK) and JNK ({delta}JNK), and siRNAs for MEK1, p42 and JNK2. TNF-{alpha}-stimulated phosphorylation of p42/p44 MAPK and JNK were attenuated by pretreatment with the inhibitors U0126 and SP600125 or transfection with dominant negative mutants of {delta}ERK and {delta}JNK. Furthermore, the involvement of NF-{kappa}B in TNF-{alpha}-induced MMP-9 production was consistent with that TNF-{alpha}-stimulated degradation of I{kappa}B-{alpha} and translocation of NF-{kappa}B into the nucleus which were blocked by helenalin, but not by U0126 and SP600125, revealed by immunofluorescence staining. The regulation of MMP-9 gene transcription by MAPKs and NF-{kappa}B was further confirmed by gene luciferase activity assay. MMP-9 promoter activity was enhanced by TNF-{alpha} in A549 cells transfected with wild-type MMP-9-Luc, which was inhibited by helenalin, U0126, or SP600125. In contrast, TNF-{alpha}-stimulated MMP-9 luciferase activity was totally lost in cells transfected with mutant-NF-{kappa}B MMP-9-luc. Moreover, pretreatment with actinomycin D and cycloheximide attenuated TNF-{alpha}-induced MMP-9 expression. These results suggest that in A549 cells, phosphorylation of p42/p44 MAPK, JNK, and transactivation of NF-{kappa}B are essential for TNF-{alpha}-induced MMP-9 gene expression.

Lin, C.-C. [Department of Anesthetics, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan (China); Tseng, Hsiao-Wei; Hsieh, Hsi-Lung; Lee, Chiang-Wen [Department of Physiology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan (China); Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan (China); Wu, C.-Y. [Department of Anesthetics, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan (China); Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan (China); Cheng, C.-Y. [Department of Physiology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan (China); Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan (China); Yang, C.-M. [Department of Physiology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan (China); Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan (China)], E-mail: chuenmao@mail.cgu.edu.tw

2008-06-15

24

Tumour necrosis factor-alpha induced CD70 and interleukin-7R mRNA expression in BEAS-2B cells.  

PubMed

Over the past few years, evidence has emerged for the potential role of the human bronchial epithelial cell in the initiation and progress of inflammation of the airway. Thus, the aim of this study was to investigate the expression pattern of cytokines and immunomodulatory factors in the human bronchial epithelial cell. To elucidate this highly complex expression and regulation pattern, the simian virus-40 transformed human bronchial-epithelial cell line BEAS-2B was stimulated with human recombinant tumour necrosis factor (hrTNF)-alpha (10 ng x mL(-1) (specific activity, 2.86 x 10(7) U x mg(-1))) and messenger ribonucleic acid (mRNA) expression pattern was analysed by complementary deoxyribonucleic acid (cDNA) array analysis. Among 375 arrayed cDNA clones, 173 (46%) were detected in BEAS-2B cells. The levels of expression of 17 genes, including those of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, growth-related oncogene (GRO) alpha, beta, gamma, interleukin (IL)-7 receptor, CD70, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and regulated in activation, normal T-cell expressed and secreted (RANTES) were elevated after TNF-alpha stimulation. The differential character of 12 clones was further characterised and verified by real time polymerase chain reaction (PCR) analysis of total ribonucleic acid (RNA) isolated from BEAS-2B cells after 4 or 16 h incubation with increasing TNF-alpha concentrations (1 pg-10 ng x mL(-1)). The authors semiquantified concentration-dependent mRNA upregulation of cytokines and immunology factors identified in the array and could determine threshold values of mRNA increases at 10 pg x mL(-1)-1 ng x mL(-1) TNF-alpha by real-time PCR. For CD70 (CD27 ligand) and interleukin-7 receptor, which to the best of the author's knowledge have not yet been described in the human bronchial epithelial cell, a rapid and continuous messenger ribonucleic acid increase induced by 100 pg x mL(-1) tumour necrosis factor-alpha after only 60-90 min was shown. A potential role for these genes in the inflammatory process in the human bronchial epithelial cell is proposed. PMID:12212969

Wolf, K; Schulz, C; Riegger, G A J; Pfeifer, M

2002-08-01

25

Tumor Necrosis Factor Alpha Enhances Influenza A Virus-Induced Expression of Antiviral Cytokines by Activating RIG-I Gene Expression  

Microsoft Academic Search

Epithelial cells of the lung are the primary targets for respiratory viruses. Virus-carried single-stranded RNA (ssRNA) can activate Toll-like receptors (TLRs) 7 and 8, whereas dsRNA is bound by TLR3 and a cytoplasmic RNA helicase, retinoic acid-inducible protein I (RIG-I). This recognition leads to the activation of host cell cytokine gene expression. Here we have studied the regulation of influenza

Sampsa Matikainen; Jukka Siren; Jorma Tissari; Ville Veckman; Jaana Pirhonen; Martina Severa; Qiang Sun; Rongtuan Lin; Seppo Meri; Gilles Uze; John Hiscott; Ilkka Julkunen

2006-01-01

26

Tumor necrosis factor. alpha. induces proteins that bind specifically to. kappa. B-like enhancer elements and regulate interleukin 2 receptor. alpha. -chain gene expression in primary human T lymphocytes  

SciTech Connect

The authors have investigated the biochemical basis for the activation of interleukin 2 receptor {alpha}-subunit (IL-2R{alpha}) gene expression in primary human T lymphocytes by a cytokine (tumor necrosis factor {alpha}), a T-cell mitogen (phorbol 12-myristate 13-acetate), and the transactivator protein (Tax) from the type I human T-cell leukemia virus. Using in vivo transfection techniques specifically designed for these primary T cells in conjunction with in vitro gel retardation and DNA footprinting assays, the authors found that activation of the IL-2R{alpha} promoter by each of these agents involves the induction of nuclear proteins that specifically interact with a {kappa}B-like enhancer element. DNA-protein crosslinking studies revealed that primary T cells express at least three different inducible DNA-binding proteins that specifically interact with this IL-2R{alpha} {kappa}B element.

Lowenthal, J.W.; Ballard, D.W.; Boehnlein, E.; Greene, W.C. (Duke Univ. Medical Center, Durham, NC (USA))

1989-04-01

27

Exogenous Nitric Oxide Inhibits Tumor Necrosis Factor-Alpha- or Interleukin1-Beta-Induced Monocyte Chemoattractant Protein1 Expression in Human Mesangial Cells  

Microsoft Academic Search

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in glomerulonephritis and nitric oxide (NO) exerts a variety of renal pathophysiological effects. We investigated the effect of exogenous NO on pro-inflammatory cytokine-induced MCP-1 expression in human mesangial cells and its signal transduction pathway. Cells were pretreated with NO donors such as 3-morpholino-sydnonimine (SIN-1) or nitroprusside, and then stimulated with tumor necrosis

Sang Koo Lee; Choung Soo Kim; Won Seok Yang; Soon Bae Kim; Su-Kil Park; Jung Sik Park

2002-01-01

28

Inhibition of tumor necrosis factor-{alpha}-induced expression of adhesion molecules in human endothelial cells by the saponins derived from roots of Platycodon grandiflorum  

SciTech Connect

Adhesion molecules play an important role in the development of atherogenesis and are produced by endothelial cells after being stimulated with various inflammatory cytokines. This study examined the effect of saponins that were isolated from the roots of Platycodon grandiflorum A. DC (Campanulaceae), Changkil saponins (CKS), on the cytokine-induced monocyte/human endothelial cell interaction, which is a crucial early event in atherogenesis. CKS significantly inhibited the TNF{alpha}-induced increase in monocyte adhesion to endothelial cells as well as decreased the protein and mRNA expression levels of vascular adhesion molecule-1 and intercellular cell adhesion molecule-1 on endothelial cells. Furthermore, CKS significantly inhibited the TNF{alpha}-induced production of intracellular reactive oxygen species (ROS) and activation of NF-{kappa}B by preventing I{kappa}B degradation and inhibiting I{kappa}B kinase activity. Overall, CKS has anti-atherosclerotic and anti-inflammatory activity, which is least in part the result of it reducing the cytokine-induced endothelial adhesion to monocytes by inhibiting intracellular ROS production, NF-{kappa}B activation, and cell adhesion molecule expression in endothelial cells.

Kim, Ji Young [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of); Kim, Dong Hee [Department of Pathology, College of Oriental Medicine, Daejeon University, Daejeon (Korea, Republic of); Kim, Hyung Gyun [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of); Song, Gyu-Yong [Department of Pharmacy, College of Pharmacy, Chungnam National University, Taejon (Korea, Republic of); Chung, Young Chul [Division of Food Science, Chinju International University, Chinju (Korea, Republic of); Roh, Seong Hwan [Jangsaeng Doraji Research Institute of Biotechnology, Jangsaeng Doraji Co., Ltd., Chinju (Korea, Republic of); Jeong, Hye Gwang [Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, Kwangju (Korea, Republic of)]. E-mail: hgjeong@chosun.ac.kr

2006-01-15

29

Molecular characterization and expression analysis of three hypoxia-inducible factor alpha subunits, HIF-1?, -2? and -3? in hypoxia-tolerant Indian catfish, Clarias batrachus [Linnaeus, 1758].  

PubMed

The present study aimed at characterization of three HIF-? subunits, HIF-1? -2? and -3? from hypoxia-tolerant Clarias batrachus, as well as to elucidate their expression pattern under short and long-term hypoxic conditions and identification of biomarker candidate. The complete cDNAs of HIF-1?, -2? and -3? were 2,833, 4,270 and 3,256 bp in length, encoding 774, 818 and 628 amino acid residues, respectively. In C. batrachus, HIF-? subunits were structurally similar in DNA binding, dimerization, degradation and transcriptional activation domains, but differed in their oxygen-dependent degradation domains. Presence of c-Jun N-terminal kinase binding domain in HIF-? subunits was reported here for the first time in fish. In adult C. batrachus, three HIF-? mRNAs were detected in different tissues under normoxic conditions, however HIF-1? was highly expressed in all the tissues studied, in comparison to HIF-2? and -3?. Short-term hypoxia exposure caused significant increase in three HIF-? transcripts in brain, liver and head kidney, while after long-term hypoxia exposure, significant up-regulation of HIF-1? in spleen and -2? in muscle was observed and HIF-3? significantly down-regulated in head kidney. These observations suggest that the differential expression of HIF-? subunits in C. batrachus was hypoxic time period dependent and may play specialized roles in adaptive response to hypoxia. HIF-2?, with its highly elevated expression in muscle tissues, can be a robust biomarker candidate for exposure to hypoxic environment. PMID:24065526

Mohindra, Vindhya; Tripathi, Ratnesh Kumar; Singh, Rajeev Kumar; Lal, Kuldeep K

2013-09-25

30

Tumor Necrosis Factor alpha Functions in an Autocrine Manner in the Induction of Human Immunodeficiency Virus Expression  

Microsoft Academic Search

Tumor necrosis factor alpha (TNF-alpha) is an immunoregulatory cytokine capable of inducing viral expression in cells chronically infected with the human immunodeficiency virus (HIV), such as the promonocytic line U1 and the T-lymphocytic line ACH-2. In the present study, we demonstrate an autocrine mechanism of TNF-alpha-mediated HIV induction. Stimulation of U1 and ACH-2 cells with phorbol 12-myristate 13-acetate (PMA) resulted

Guido Poli; Audrey Kinter; Jesse S. Justement; John H. Kehrl; Peter Bressler; Sharilyn Stanley; Anthony S. Fauci

1990-01-01

31

Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages  

PubMed Central

Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-?) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-? expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-? protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 ?M). (iii) Inhibition by bikunin of TNF-? induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-? target molecules interleukin-1? (IL-1?) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-? release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-? production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

Matsuzaki, Hidenori; Kobayashi, Hiroshi; Yagyu, Tatsuo; Wakahara, Kiyoshi; Kondo, Toshiharu; Kurita, Noriyuki; Sekino, Hideo; Inagaki, Kiyokazu; Suzuki, Mika; Kanayama, Naohiro; Terao, Toshihiko

2004-01-01

32

Increased Leptin Expression in Mice with Bacterial Peritonitis is Partially Regulated by Tumor Necrosis Factor Alpha  

Microsoft Academic Search

Plasma leptin and ob gene mRNA levels were increased in mice following bacterial peritonitis, and blocking an endogenous tumor necrosis factor alpha (TNF-a) response blunted the increase. However, plasma leptin concentrations did not correlate with the associated anorexia. We conclude that leptin expression is under partial regulatory control of TNF-a in peritonitis, but the anorexia is not dependent on increased

ARMIN K. MOSHYEDI; MICHAEL D. JOSEPHS; EDDIE K. ABDALLA; SALLY L. D. MACKAY; CARL K. EDWARDS; EDWARD M. COPELAND; LYLE L. MOLDAWER

1998-01-01

33

Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes  

Microsoft Academic Search

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNF?), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of

Jean Frédéric Boyer; Patricia Balard; Hélène Authier; Bruno Faucon; José Bernad; Bernard Mazières; Jean-Luc Davignon; Alain Cantagrel; Bernard Pipy; Arnaud Constantin

2007-01-01

34

Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis.  

PubMed

Paracetamol-induced hepatic necrosis is the most common form of toxic liver injury experienced in clinical practice in the UK and USA. Recently, reports have described prevention of hepatic necrosis, induced by other hepato-toxins, by inhibiting tumour necrosis factor alpha (TNFalpha). The aim of the present study was to determine the role of TNFalpha in paracetamol-induced hepatic necrosis. Six-week-old CBA/J female mice were given 300 mg/kg paracetamol by intraperitoneal (IP) injection after an 8-h fast. Hepatic expression of TNFalpha was measured by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR). Serum TNFalpha was measured by ELISA. One hour prior to paracetamol injection, mice were also given blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, interleukin 10 (IL-10), and dexamethasone. Hepatic injury was measured by serum aspartate aminotransferase and histological assessment on haematoxylin and eosin (H&E)-stained liver sections. There was a significant increase in serum TNFalpha at 6 h (control 0.002+/-0.002 ng/ml, n=7; paracetamol-treated 0.022+/-0.007 ng/ml, n=5, p<0.05), but hepatic TNFalpha expression did not change up to 24 h following paracetamol injection. Histologically severe centrilobular hepatic necrosis was noted at 3 h and progressed for 24 h after paracetamol poisoning. Death rate, serum aspartate aminotransferase, and hepatic histology were not significantly different between the groups treated with blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, IL-10, and dexamethasone, compared with controls. In conclusion, there is no evidence to suggest that modulation of TNFalpha expression affects hepatic injury following experimental paracetamol poisoning; anti-TNFalpha therapies are therefore unlikely to be effective in the corresponding clinical situation. PMID:10700000

Simpson, K J; Lukacs, N W; McGregor, A H; Harrison, D J; Strieter, R M; Kunkel, S L

2000-03-01

35

Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations.  

PubMed Central

Tumor necrosis factor-alpha (TNF) has been implicated strongly as a principal mediator in the pathogenesis of septic shock. The authors investigated the in vivo production of TNF in CBA/J and CD-1 mice that had been primed by an intraperitoneal injection of complete Freund's adjuvant followed 2 weeks later by an intraperitoneal injection of lipopolysaccharide (LPS). TNF bioactivity peaked in both the ascites and plasma one hour after challenge, and TNF mRNA expression in the ascites cells peaked 30 minutes after LPS. After the induction of bioactivity, an interstitial pulmonary neutrophilic infiltrate occurred that was quantitated both morphometrically and by a myeloperoxidase (MPO) assay. Peripheral blood neutrophilia and lymphopenia developed after the LPS injection (PMNs: control, 46 +/- 2%; LPS, 65 +/- 3%; Lymphs control, 53 +/- 2%; LPS, 37 +/- 3%). Treatment with dexamethasone (Dex) completely inhibited the pulmonary neutrophilic infiltrate as measured by the (MPO) assay. Because Dex will inhibit the production of several cytokines, anti-TNF antiserum was given to mice at the same time as the LPS challenge to assess specifically the role of TNF in inducing these changes. This antiserum partially blocked the pulmonary neutrophil infiltrate, and completely blocked the peripheral blood changes at one hour after LPS. These data demonstrate that TNF plays an important role in the early pathophysiologic alterations that occur after systemic exposure to LPS. Images Figure 3 Figure 4 Figure 6 Figure 11

Remick, D. G.; Strieter, R. M.; Eskandari, M. K.; Nguyen, D. T.; Genord, M. A.; Raiford, C. L.; Kunkel, S. L.

1990-01-01

36

Tumor necrosis factor-alpha-induced cell death in U373 cells overexpressing alpha-synuclein.  

PubMed

Intracellular alpha-synuclein inclusion formation in glial cells is frequently seen in Parkinson's disease and multiple system atrophy. Microglial activation in these neurodegenerative disorders suggests that neuroinflammatory responses might interact with alpha-synuclein and contribute to the pathogenesis of these disorders. To study the role of tumor necrosis factor-alpha (TNF-alpha), an important proinflammatory cytokine produced by microglia, on cells overexpressing alpha-synuclein we have used the astrocytoma cell line U373 engineered to express C-terminally truncated alpha-synuclein as a fusion protein with red or green fluorescent proteins. We demonstrate that alpha-synuclein overexpression augmented TNF-alpha-induced apoptotic cell death in U373 cells by induction of caspase activation. Furthermore, TNF-alpha exposure was associated with significant cytoskeletal changes characterized by altered inclusion composition with loss of cytoskeletal proteins and elevation of high-molecular-weight alpha-synuclein species. We conclude that alpha-synuclein overexpression significantly increases the vulnerability of U373 cells to apoptosis through TNF-alpha-mediated pathways. PMID:12868067

Stefanova, Nadia; Schanda, Kathrin; Klimaschewski, Lars; Poewe, Werner; Wenning, Gregor K; Reindl, Markus

2003-08-01

37

Postnatal lung function and morphology in transgenic mice expressing transforming growth factor-alpha.  

PubMed Central

Developmental changes in lung morphology and physiology during postnatal alveolarization were assessed in transgenic mice expressing transforming growth factor-alpha (TGF-alpha) in pulmonary type II cells under control of the surfactant protein C gene promoter. TGF-alpha transcripts were identified in respiratory epithelial cells at 1 day of age to adulthood. Enlargement of alveolar airspaces and fibrosis were detected as early as 1 week of age, and the increased airspace progressed with advancing age. Specific lung compliance was significantly increased in lungs of transgenic mice by 2 weeks of age and was associated with airflow obstruction. Chronic expression of TGF-alpha in the lungs of newborn transgenic mice caused remodeling of the developing lung during the period of postnatal alveolarization, resulting in markedly enlarged parenchymal airspace, pulmonary fibrosis, and physiological abnormalities including airway obstruction and increased lung compliance. Images Figure 1 Figure 2 Figure 3

Hardie, W. D.; Bruno, M. D.; Huelsman, K. M.; Iwamoto, H. S.; Carrigan, P. E.; Leikauf, G. D.; Whitsett, J. A.; Korfhagen, T. R.

1997-01-01

38

Downregulation of phorbol 12-myristate 13-acetate—induced tumor necrosis factor—alpha and interleukin-1? production and gene expression in human monocytic cells by human alpha-fetoprotein  

Microsoft Academic Search

We previously identified a specific receptor for alphafetoprotein (AFP) on human monocytes. Although AFP alters many immune cell functions, the effect of AFP on monocyte cytokine production is unknown. Because tumor necrosis factor-alpha (TNF-?) and interleukin-1? (IL-1?) are important cytokines in immunoregulation, we investigated whether AFP could modulate TNF-? and IL-1? production in U937, a human monocytic cell line. Our

Wei Wang; Elliot Alpert

1995-01-01

39

Tumor necrosis factor-alpha decreases aquaporin-3 expression in DJM-1 keratinocytes.  

PubMed

Aquaporin-3 (AQP3) is a water/glycerol-transporting protein that is strongly expressed at the plasma membranes of keratinocytes in skin. There is evidence for involvement of AQP3-facilitated water and glycerol transport in skin hydration and wound repair, respectively. In this study, we show that tumor necrosis factor-alpha (TNF-alpha) and TNF receptor-1 signaling decreased AQP3 protein expression and plasma membrane water permeability in DJM-1 keratinocytes. TNF-alpha also decreased AQP3 mRNA expression and promoter activity, indicating that TNF-alpha suppresses AQP3 gene transcription. In addition, inhibitors of p38 and extracellular signal-regulated kinase (ERK) abolished the effect of TNF-alpha on AQP3 expression level, whereas inhibitors for NF-kappaB did not. These data indicate that TNF-alpha decreases AQP3 gene expression through p38 and ERK activation, and suggest that the decrease in AQP3 expression caused by TNF-alpha might be related to the phenotypes of skin inflammation, such as dry skin. PMID:19619514

Horie, Ichiro; Maeda, Mamiko; Yokoyama, Satoshi; Hisatsune, Akinori; Katsuki, Hiroshi; Miyata, Takeshi; Isohama, Yoichiro

2009-07-18

40

Transcription Factor AP2  Is Preferentially Cleaved by Caspase 6 and Degraded by Proteasome during Tumor Necrosis Factor Alpha-Induced Apoptosis in Breast Cancer Cells  

Microsoft Academic Search

Several reports have linked activating protein 2a (AP-2a) to apoptosis, leading us to hypothesize that AP-2a is a substrate for caspases. We tested this hypothesis by examining the effects of tumor necrosis factor alpha (TNF-a) on the expression of AP-2 in breast cancer cells. Here, we provide evidence that TNF-a downregulates AP-2a and AP-2g expression posttranscriptionally during TNF-a-induced apoptosis. Both

OKOT NYORMOI; ZHI WANG; DAO DOAN; MARIBELIS RUIZ; DAVID MCCONKEY; MENASHE BAR-ELI

2001-01-01

41

Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes  

PubMed Central

In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNF?), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNF? and adalimumab, a human anti-TNF? monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNF? or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)? in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNF? inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPAR? activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNF? and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.

Boyer, Jean Frederic; Balard, Patricia; Authier, Helene; Faucon, Bruno; Bernad, Jose; Mazieres, Bernard; Davignon, Jean-Luc; Cantagrel, Alain; Pipy, Bernard; Constantin, Arnaud

2007-01-01

42

Tumor necrosis factor alpha regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats.  

PubMed

Anti-tumor necrosis factor alpha (TNF-alpha) treatment decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric oxide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is responsible for the increased susceptibility of the mucosa to damage. In the present study, we examined whether TNF-alpha is overexpressed in portal hypertensive gastric mucosa and whether anti-TNF-alpha treatment affects gastric NOS3 messenger RNA (mRNA) and protein expression. We examined plasma concentrations of TNF-alpha and its protein expression in gastric specimens from portal hypertensive and sham-operated rats using Western blotting and immunohistochemistry. We also measured gastric mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-alpha-neutralizing antibody treatment. The TNF-alpha protein levels in portal hypertensive stomachs were significantly increased by 57% compared with levels in sham-operated controls. TNF-alpha antibody treatment normalized gastric mucosal blood flow in portal hypertensive stomachs and significantly reversed overexpression of gastric NOS3 mRNA, protein, and its enzyme activity in portal hypertensive rats by 48%, 45%, and 33%, respectively. These results suggest that TNF-alpha may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-alpha treatment may ameliorate the pathophysiological abnormalities of portal hypertensive gastric mucosa. PMID:9537427

Ohta, M; Tarnawski, A S; Itani, R; Pai, R; Tomikawa, M; Sugimachi, K; Sarfeh, I J

1998-04-01

43

Diesel exhaust particles induce the over expression of tumor necrosis factor-alpha (TNF-alpha) gene in alvelor machrophage and failed to induce apoptosis through activation of nuclear factor-kappaB (NF-kappaB)  

EPA Science Inventory

Exposure to particulate matter (PM2.5-10), including diesel exhaust particles (DEP) has been reported to induce lung injury and exacerbation of asthma and chronic obstructive pulmonary disease. Alveolar macrophages play a major role in the lung's response to inhaled particles and...

44

Glutathione regulation of redox-sensitive signals in tumor necrosis factor-{alpha}-induced vascular endothelial dysfunction  

SciTech Connect

We investigated the regulatory role of glutathione in tumor necrosis factor-alpha (TNF-{alpha})-induced vascular endothelial dysfunction as evaluated by using vascular endothelial adhesion molecule expression and monocyte-endothelial monolayer binding. Since TNF-{alpha} induces various biological effects on vascular cells, TNF-{alpha} dosage could be a determinant factor directing vascular cells into different biological fates. Based on the adhesion molecule expression patterns responding to different TNF-{alpha} concentrations, we adopted the lower TNF-{alpha} (0.2 ng/ml) to rule out the possible involvement of other TNF-{alpha}-induced biological effects. Inhibition of glutathione synthesis by L-buthionine-(S,R)-sulfoximine (BSO) resulted in down-regulations of the TNF-{alpha}-induced adhesion molecule expression and monocyte-endothelial monolayer binding. BSO attenuated the TNF-{alpha}-induced nuclear factor-kappaB (NF-{kappa}B) activation, however, with no detectable effect on AP-1 and its related mitogen-activated protein kinases (MAPKs). Deletion of an AP-1 binding site in intercellular adhesion molecule-1 (ICAM-1) promoter totally abolished its constitutive promoter activity and its responsiveness to TNF-{alpha}. Inhibition of ERK, JNK, or NF-{kappa}B attenuates TNF-{alpha}-induced ICAM-1 promoter activation and monocyte-endothelial monolayer binding. Our study indicates that TNF-{alpha} induces adhesion molecule expression and monocyte-endothelial monolayer binding mainly via activation of NF-{kappa}B in a glutathione-sensitive manner. We also demonstrated that intracellular glutathione does not modulate the activation of MAPKs and/or their downstream AP-1 induced by lower TNF-{alpha}. Although AP-1 activation by the lower TNF-{alpha} was not detected in our systems, we could not rule out the possible involvement of transiently activated MAPKs/AP-1 in the regulation of TNF-{alpha}-induced adhesion molecule expression.

Tsou, T.-C. [Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China)]. E-mail: tctsou@nhri.org.tw; Yeh, S.C. [Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Tsai, F.-Y. [Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Chen, J.-W. [Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China); Chiang, H.-C. [Laboratory of Molecular Toxicology, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan (China)

2007-06-01

45

TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)  

EPA Science Inventory

TITLE: TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

46

Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain  

Microsoft Academic Search

Background and Objectives: Evidence implicates the pleiotropic cytokine tumor necrosis factor alpha (TNF?) in the pathogenesis of persistent pain. The present study employs a chronic constriction injury (CCI) model of neuropathic pain to examine TNF? production in the central nervous system (CNS) and in the periphery in this pain model. Methods: CCI-induced hyperalgesia is assessed by measuring the nociceptive threshold

William C. Covey; Tracey A. Ignatowski; Amy E. Renauld; Paul R. Knight; Nader D. Nader; Robert N. Spengler

2002-01-01

47

Cinnamaldehyde inhibits the tumor necrosis factor-{alpha}-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-{kappa}B activation: Effects upon I{kappa}B and Nrf2  

SciTech Connect

The production of adhesion molecules and subsequent attachment of leukocytes to endothelial cells (ECs) are critical early events in atherogenesis. These adhesion molecules thus play an important role in the development of this disease. Recent studies have highlighted the chemoprotective and anti-inflammatory effects of cinnamaldehyde, a Cinnamomum cassia Presl-specific diterpene. In our current study, we have examined the effects of both cinnamaldehyde and extracts of C. cassia on cytokine-induced monocyte/human endothelial cell interactions. We find that these compounds inhibit the adhesion of TNF{alpha}-induced monocytes to endothelial cells and suppress the expression of the cell adhesion molecules, VCAM-1 and ICAM-1, at the transcriptional level. Moreover, in TNF{alpha}-treated ECs, the principal downstream signal of VCAM-1 and ICAM-1, NF-{kappa}B, was also found to be abolished in a time-dependent manner. Interestingly, cinnamaldehyde exerts its anti-inflammatory effects by blocking the degradation of the inhibitory protein I{kappa}B-{alpha}, but only in short term pretreatments, whereas it does so via the induction of Nrf2-related genes, including heme-oxygenase-1 (HO-1), over long term pretreatments. Treating ECs with zinc protoporphyrin, a HO-1 inhibitor, partially blocks the anti-inflammatory effects of cinnamaldehyde. Elevated HO-1 protein levels were associated with the inhibition of TNF{alpha}-induced ICAM-1 expression. In addition to HO-1, we also found that cinnamaldehyde can upregulate Nrf2 in nuclear extracts, and can increase ARE-luciferase activity and upregulate thioredoxin reductase-1, another Nrf2-related gene. Moreover, cinnamaldehyde exposure rapidly reduces the cellular GSH levels in ECs over short term treatments but increases these levels after 9 h exposure. Hence, our present findings indicate that cinnamaldehyde suppresses TNF-induced singling pathways via two distinct mechanisms that are activated by different pretreatment periods.

Liao, B.-C.; Hsieh, C.-W. [Department of Microbiology and Immunology, National Chiayi University, Chiayi, Taiwan (China); Liu, Y.-C. [Institute of Biotechnology, National Chiayi University, Chiayi, Taiwan (China); Tzeng, T.-T. [Department of Microbiology and Immunology, National Chiayi University, Chiayi, Taiwan (China); Sun, Y.-W. [Department of Biotechnology, Seed Improvement and Propagation Station, Taichung, Taiwan (China); Wung, B.-S. [Department of Microbiology and Immunology, National Chiayi University, Chiayi, Taiwan (China)], E-mail: bswung@mail.ncyu.edu.tw

2008-06-01

48

Adrenomedullin suppresses tumour necrosis factor alpha-induced CXC chemokine ligand 10 production by human gingival fibroblasts  

PubMed Central

Periodontal disease is an inflammatory disorder characterized by the involvement of chemokines that are important for the recruitment of leucocytes. Several cytokines, including tumour necrosis factor alpha (TNF-?), are involved in regulating levels of chemokines in periodontal disease. CXC chemokine ligand 10 (CXCL10) is a chemokine related to the migration of T helper 1 cells. In this study, we examined CXCL10 expression in human gingival fibroblasts (HGFs). Moreover, we investigated the effects of adrenomedullin (AM), which is a multi-functional regulatory peptide, on the production of CXCL10 by HGFs. We revealed that TNF-? stimulation induced CXCL10 production by HGFs. HGFs expressed AM and AM receptors, calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) 2, mRNAs constitutively. AM treatment supressed CXCL10 production by TNF-?-stimulated HGFs. Moreover, we elucidated that AM produced by HGFs inhibited CXCL10 production by HGFs, because AM antagonist enhanced CXCL10 production by HGFs. TNF-? treatment enhanced CRLR and RAMP2 mRNA expression in HGFs. Furthermore, AM is expressed in human periodontal tissues, including both inflamed and clinically healthy tissues. These results suggest that the CXCL10 produced by HGFs may be involved in the migration of leucocytes into inflamed tissues and related to exacerbation of periodontal disease. AM might be a therapeutic target of periodontal disease, because AM can inhibit CXCL10 production by HGFs.

Hosokawa, I; Hosokawa, Y; Ozaki, K; Nakae, H; Matsuo, T

2008-01-01

49

Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis.  

PubMed

Transforming growth factor-alpha (TGFalpha) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3'-kinase (PI3K). We previously showed that induction of lung-specific TGFalpha expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFalpha expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFalpha induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFalpha prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy. PMID:20042669

Le Cras, Timothy D; Korfhagen, Thomas R; Davidson, Cynthia; Schmidt, Stephanie; Fenchel, Matthew; Ikegami, Machiko; Whitsett, Jeffrey A; Hardie, William D

2009-12-30

50

Streptococcal Histone Induces Murine Macrophages To Produce Interleukin-1 and Tumor Necrosis Factor Alpha  

PubMed Central

The histone-like protein (HlpA) is highly conserved among streptococci. After lysis of streptococci in infected tissues, HlpA can enter the bloodstream and bind to proteoglycans in the glomerular capillaries of kidneys, where it can react with antibodies or stimulate host cell receptors. Deposits of streptococcal antigens in tissues have been associated with localized acute inflammation. In this study, we measured the ability of purified HlpA (5 to 100 ?g/ml), from Streptococcus mitis, to induce the production of proinflammatory cytokines by cultured, murine peritoneal macrophages. The release of tumor necrosis factor alpha (TNF-?) and interleukin-1 (IL-1) was time and concentration dependent and was not diminished by the presence of polymyxin B. Exposure of macrophages to a mixture of HlpA and lipoteichoic acid resulted in a synergistic response in the production of both TNF-? and IL-1. Stimulation with a mixture of HlpA and heparin resulted in reduced cytokine production (50% less IL-1 and 76% less TNF-?) compared to that by cells incubated with HlpA alone. The inclusion of antibodies specific to HlpA in macrophage cultures during stimulation with HlpA did not affect the quantity of TNF-? or IL-1 produced. These observations suggest that streptococcal histone may contribute to tissue injury at infection sites by promoting monocytes/macrophages to synthesize and release cytokines that initiate and exacerbate inflammation. Streptococcus pyogenes, which can infect tissues in enormous numbers, may release sufficient amounts of HlpA to reach the kidneys and cause acute poststreptococcal glomerulonephritis.

Zhang, Liping; Ignatowski, Tracey A.; Spengler, Robert N.; Noble, Bernice; Stinson, Murray W.

1999-01-01

51

Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells.  

PubMed Central

Proinflammatory cytokines released by hepatic macrophages (Kupffer cells) have a central role in the pathogenesis of liver injury and the cardiovascular abnormalities of sepsis. Because cytokine release is controlled primarily at the level of gene expression, intracellular signalling mechanisms that control the transcription of cytokine genes are critical links to organ injury. Oxidant stress up-regulates and antioxidants down-regulate the pleiotropic transcription factor NF-kappa B, a DNA-binding protein that induces the expression of cytokines and vascular adhesion molecules. Thiol-bearing molecules are also important inhibitors of NF-kappa B activation, but whether this inhibition represents an antioxidant effect is unknown. This study was undertaken to determine whether important endogenous and pharmacological thiols modulate the activation of NF-kappa B and the release of tumour necrosis factor alpha (TNF-alpha) from Kupffer cells and to ascertain whether these effects are mediated through glutathione. Exposure of rat Kupffer cells to a physiologically relevant concentration of lipopolysaccharide (10 ng/ml) activated NF-kappa B within 1 h and induced the release of TNF-alpha over 5 h. Cellular glutathione content remained unchanged after lipopolysaccharide exposure, but both glutathione monoethyl ester and N-acetyl-L-cysteine increased cellular glutathione levels, blocked NF-kappa B activation and inhibited the release of TNF-alpha. Inhibition of glutathione synthesis prevented the NAC-induced increase in Kupffer cell glutathione, yet it did not prevent the inhibition of TNF-alpha release by NAC. Thus the inhibition of NF-kappa B activation by pharmacological thiols such as NAC might reflect a more general role of the intracellular thiol redox status in NF-kappa B regulation rather than the antioxidant properties of these agents.

Neuschwander-Tetri, B A; Bellezzo, J M; Britton, R S; Bacon, B R; Fox, E S

1996-01-01

52

Species differences in the expression of transforming growth factor-alpha (TGF-?) in the submandibular gland and pancreas  

Microsoft Academic Search

Summary\\u000a Conclusion  \\u000a Significant differences exist in the expression of transforming growth factor-alpha (TGF-?) in the submandibular glands (SMG)\\u000a and the pancreas of different species and among cell components in the same species.\\u000a \\u000a \\u000a \\u000a Background  Our previous studies have shown marked differences in the expression of TGF-? in the pancreas of humans and Syrian hamsters.\\u000a To examine whether these differences also exist in

Yoshito Ikematsu; Parviz M. Pour; Katherine Kazakoff

1997-01-01

53

Rhinovirus Replication in Human Macrophages Induces NF B-Dependent Tumor Necrosis Factor Alpha Production  

Microsoft Academic Search

Rhinoviruses (RV) are the major cause of acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Rhinoviruses have been shown to activate macrophages, but rhinovirus replication in macrophages has not been reported. Tumor necrosis factor alpha (TNF-) is implicated in the pathogenesis of acute exacerbations, but its cellular source and mechanisms of induction by virus infection are unclear. We

Vasile Laza-Stanca; Luminita A. Stanciu; Simon D. Message; Michael R. Edwards; James E. Gern; Sebastian L. Johnston

2006-01-01

54

Two coordinated mechanisms underlie tumor necrosis factor alpha-induced immediate and delayed I?B kinase activation.  

PubMed

Tumor necrosis factor alpha (TNF-?)-induced NF-?B activation has been believed to depend on TRAF2- and cIAP1-mediated RIP1 ubiquitination. However, recent findings have challenged the notion that these proteins play essential roles in NF-?B activation. Here, by assessing the kinetics and amplitude of I?B kinase (IKK) activation, we report that TNF-?-induced immediate and robust activation of IKK requires K63-linked and linearly linked ubiquitination of RIP1 and that in the absence of RIP1 expression, TRAF2 and cIAP1 cooperatively induce delayed IKK activation by recruiting LUBAC to TNFR1. Knockdown of HOIP (a component of LUBAC) in RIP1-deficient cells completely impairs the recruitment and activation of IKK but does not affect K63-linked ubiquitination of TRAF2 and recruitment of TAK1 to TNFR1, suggesting that the K63-linked ubiquitin chain is not capable of recruiting IKK in vivo. We also demonstrate that TRAF2 and cIAP1 together, but not either one alone, directly catalyze linearly linked ubiquitination of RIP1. Importantly, in embryonic hepatocytes, TNF-? activates NF-?B through a RIP1-independent pathway. Thus, our findings clarify molecular details of this important signaling mechanism by providing evidence for the existence of two phases of IKK activation: the immediate phase, induced by TRAF2/cIAP1-mediated ubiquitination of RIP1, and the delayed phase, activated by TRAF2/cIAP1-dependent recruitment of LUBAC. PMID:23459942

Blackwell, Ken; Zhang, Laiqun; Workman, Lauren M; Ting, Adrian T; Iwai, Kazuhiro; Habelhah, Hasem

2013-03-04

55

Shiga Toxin 1-Induced Inflammatory Response in Lipopolysaccharide-Sensitized Astrocytes Is Mediated by Endogenous Tumor Necrosis Factor Alpha?  

PubMed Central

Hemolytic-uremic syndrome (HUS) is generally caused by Shiga toxin (Stx)-producing Escherichia coli. Endothelial dysfunction mediated by Stx is a central aspect in HUS development. However, inflammatory mediators such as bacterial lipopolysaccharide (LPS) and polymorphonuclear neutrophils (PMN) contribute to HUS pathophysiology by potentiating Stx effects. Acute renal failure is the main feature of HUS, but in severe cases, patients can develop neurological complications, which are usually associated with death. Although the mechanisms of neurological damage remain uncertain, alterations of the blood-brain barrier associated with brain endothelial injury is clear. Astrocytes (ASTs) are the most abundant inflammatory cells of the brain that modulate the normal function of brain endothelium and neurons. The aim of this study was to evaluate the effects of Stx type 1 (Stx1) alone or in combination with LPS in ASTs. Although Stx1 induced a weak inflammatory response, pretreatment with LPS sensitized ASTs to Stx1-mediated effects. Moreover, LPS increased the level of expression of the Stx receptor and its internalization. An early inflammatory response, characterized by the release of tumor necrosis factor alpha (TNF-?) and nitric oxide and PMN-chemoattractant activity, was induced by Stx1 in LPS-sensitized ASTs, whereas activation, evidenced by higher levels of glial fibrillary acid protein and cell death, was induced later. Furthermore, increased adhesion and PMN-mediated cytotoxicity were observed after Stx1 treatment in LPS-sensitized ASTs. These effects were dependent on NF-?B activation or AST-derived TNF-?. Our results suggest that TNF-? is a pivotal effector molecule that amplifies Stx1 effects on LPS-sensitized ASTs, contributing to brain inflammation and leading to endothelial and neuronal injury.

Landoni, Veronica I.; de Campos-Nebel, Marcelo; Schierloh, Pablo; Calatayud, Cecilia; Fernandez, Gabriela C.; Ramos, M. Victoria; Rearte, Barbara; Palermo, Marina S.; Isturiz, Martin A.

2010-01-01

56

Tumor necrosis factor alpha may act as an intraovarian mediator of luteinizing hormone-induced oocyte maturation in trout.  

PubMed

In fish, like in other vertebrates, luteinizing hormone (Lh) is an essential hormone for the completion of oocyte maturation. In salmonid fish (i.e., salmon and trout), oocyte maturation is induced by Lh through its stimulation of the production of the maturation-inducing steroid, 17alpha,20beta-dihydroxy-4-pregnen-3-one (17,20beta-P). In mammals, several factors, including ovarian cytokines and growth factors, have been reported to contribute to the regulation of oocyte maturation. In fish, growing evidence suggests that tumor necrosis factor alpha (hereafter referred to as Tnf) could play multiple physiological roles in the control of ovarian function. In the present study, we have investigated the possible involvement of Tnf in the regulation of oocyte maturation in brown trout (Salmo trutta). Our results show that in vitro treatment of brown trout preovulatory follicles with coho salmon (Oncorhynchus kisutch) Lh (sLh) significantly increased oocyte maturation, as assessed by germinal vesicle breakdown (GVBD), and that this effect was blocked by TAPI-1 (an inhibitor of Tnf-converting enzyme or Tace/Adam17). Furthermore, treatment of preovulatory follicles with sLh increased the expression of tnf and tace/adam17 as well as the secretion of the Tnf protein. Importantly, recombinant trout Tnf (rtTnf) significantly increased GVBD in vitro. Our results also show that the stimulatory effects of rtTnf on oocyte maturation may be the result of the direct involvement of rtTnf in stimulating the production of the maturation-inducing steroid as evidenced, first, by the stimulatory effects of rtTnf on 17,20beta-P production in vitro and on the expression of cholesterol side-chain cleavage P450 cytochrome (p450scc) and 20beta-hydroxysteroid dehydrogenase/carbonyl reductase 1 (cbr1), the enzyme responsible for the production of 17,20beta-P, and, second, by the ability of TAPI-1 to block the stimulatory effects of sLh on 17,20beta-P production and cbr1 expression. Furthermore, sLh and rtTnf increased the expression of the Lh receptor (lhr) and decreased the expression of aromatase (cyp19a1), and TAPI-1 completely blocked the effects of sLh. These results strongly suggest that Tnf may contribute to the regulation of oocyte maturation by Lh in trout. PMID:21880947

Crespo, Diego; Mañanós, Evaristo L; Roher, Nerea; MacKenzie, Simon A; Planas, Josep V

2012-01-10

57

The role of fatty acids and caveolin-1 in tumor necrosis factor alpha-induced endothelial cell activation.  

PubMed

Hypertriglyceridemia and associated high circulating free fatty acids are important risk factors for atherosclerosis. In contrast to omega-3 fatty acids, linoleic acid, the major omega-6 unsaturated fatty acid in the American diet, may be atherogenic by amplifying an endothelial inflammatory response. We hypothesize that omega-6 and omega-3 fatty acids can differentially modulate tumor necrosis factor alpha (TNF-alpha)-induced endothelial cell activation and that functional plasma membrane microdomains called caveolae are required for endothelial cell activation. Caveolae are particularly abundant in endothelial cells and play a major role in endothelial trafficking and the regulation of signaling pathways associated with the pathology of vascular diseases. To test our hypothesis, endothelial cells were preenriched with either linoleic acid or alpha-linolenic acid before TNF-alpha-induced endothelial activation. Measurements included oxidative stress and nuclear factor kappaB-dependent induction of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) under experimental conditions with intact caveolae and with cells in which caveolin-1 was silenced by small interfering RNA. Exposure to TNF-alpha induced oxidative stress and inflammatory mediators, such as p38 mitogen-activated protein kinase (MAPK), nuclear factor kappaB, COX-2, and PGE(2), which were all amplified by preenrichment with linoleic acid but blocked or reduced by alpha-linolenic acid. The p38 MAPK inhibitor SB203580 blocked TNF-alpha-mediated induction of COX-2 protein expression, suggesting a regulatory mechanism through p38 MAPK signaling. Image overlay demonstrated TNF-alpha-induced colocalization of TNF receptor type 1 with caveolin-1. Caveolin-1 was significantly induced by TNF-alpha, which was further amplified by linoleic acid and blocked by alpha-linolenic acid. Furthermore, silencing of the caveolin-1 gene completely blocked TNF-alpha-induced production of COX-2 and PGE(2) and significantly reduced the amplified response of linoleic acid plus TNF-alpha. These data suggest that omega-6 and omega-3 fatty acids can differentially modulate TNF-alpha-induced inflammatory stimuli and that caveolae and its fatty acid composition play a regulatory role during TNF-alpha-induced endothelial cell activation and inflammation. PMID:18803934

Wang, Lei; Lim, Eun-Jin; Toborek, Michal; Hennig, Bernhard

2008-10-01

58

Oxidative modification of IkappaB by monochloramine inhibits tumor necrosis factor alpha-induced NF-kappaB activation.  

PubMed

We have previously reported that monochloramine (NH(2)Cl), a neutrophil-derived oxidant, inhibited tumor necrosis factor alpha (TNFalpha)-induced expression of cell adhesion molecules and nuclear factor-kappaB (NF-kappaB) activation (Free Radical Research 36 (2002) 845-852). Here, we studied the mechanism how NH(2)Cl inhibited TNFalpha-induced NF-kappaB activation, and compared the effects with taurine chloramine (Tau-NHCl). Pretreatment of Jurkat cells with NH(2)Cl at 70 microM resulted in suppression of TNFalpha-induced IkappaB phosphorylation and degradation, and inhibited NF-kappaB activation. In addition, a slow-moving IkappaB band appeared on SDS-PAGE. By contrast, Tau-NHCl for up to 200 microM had no effects. Interestingly, NH(2)Cl did not inhibit IkappaB kinase activation by TNFalpha. Protein phosphatase activity did not show apparent change. When recombinant IkappaB was oxidized by NH(2)Cl in vitro and phosphorylated by TNFalpha-stimulated Jurkat cell lysate, its phosphorylation occurred less effectively than non-oxidized IkappaB. In addition, when NF-kappaB-IkappaB complex was immunoprecipitated from NH(2)Cl-treated cells and phosphorylated in vitro by recombinant active IkappaB kinase, native IkappaB but not oxidized IkappaB was phosphorylated. Amino acid analysis of the in vitro oxidized IkappaB showed methionine oxidation to methionine sulfoxide. Although Tau-NHCl alone had little effects on TNFalpha-induced NF-kappaB activation, simultaneous presence of Tau-NHCl and ammonium ion significantly inhibited the NF-kappaB activation, probably through the conversion of Tau-NHCl to NH(2)Cl. These results indicated that NH(2)Cl inhibited TNFalpha-induced NF-kappaB activation through the oxidation of IkappaB, and that NH(2)Cl is physiologically more relevant than Tau-NHCl in modifying NF-kappaB-mediated cellular responses. PMID:16344117

Ogino, Tetsuya; Hosako, Mutsumi; Hiramatsu, Kazuhisa; Omori, Masako; Ozaki, Michitaka; Okada, Shigeru

2005-10-28

59

Overexpression of tumor necrosis factor-alpha diminishes pulmonary fibrosis induced by bleomycin or transforming growth factor-beta.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) is thought to be important in the development of pulmonary fibrosis. However, surfactant protein-C/TNF-alpha transgenic mice do not spontaneously develop pulmonary fibrosis but instead develop alveolar enlargement and loss of elastic recoil. We hypothesized that overexpression of TNF-alpha in the lung requires an additional insult to produce fibrosis. In this study we evaluated whether TNF-alpha overexpression altered the development of pulmonary fibrosis due to bleomycin or transforming growth factor-beta (TGF-beta). Either 0.2 U bleomycin or saline was administered into left lung of TNF-alpha transgenic mice and their transgene-negative littermates. To overexpress TGF-beta, an adenovirus vector containing either active TGF-beta (AdTGF-beta) or LacZ was administered at a dose of 3 x 108 plaque-forming units per mouse. Fibrosis was assessed histologically and by measurement of hydroxyproline. TNF-alpha transgenic mice tolerated bleomycin or AdTGF-beta, whereas the transgene-negative littermates demonstrated severe pulmonary fibrosis after either agent. An increase in prostaglandin E2 and downregulation of TNF receptor I expression were observed in the TNF-alpha transgenic mice. In addition, recombinant human TNF-alpha attenuated bleomycin-induced pulmonary fibrosis. TNF-alpha has a complex role in the development of pulmonary fibrosis. Endogenous TNF-alpha may be important in the development of fibrosis as indicated in other reports, but overexpression of TNF-alpha or exogenous TNF-alpha limits pulmonary fibrosis in mice. PMID:12816730

Fujita, Masaki; Shannon, John M; Morikawa, Osamu; Gauldie, Jack; Hara, Nobuyuki; Mason, Robert J

2003-06-19

60

Involvement of Mst1 in tumor necrosis factor-{alpha}-induced apoptosis of endothelial cells  

SciTech Connect

Mammalian sterile 20-kinase 1 (Mst1), a member of the sterile-20 family protein kinase, plays an important role in the induction of apoptosis. However, little is know about the physiological activator of Mst1 and the role of Mst1 in endothelial cells (ECs). We examined whether Mst1 is involved in the tumor necrosis factor (TNF)-{alpha}-induced apoptosis of ECs. Western blot analysis revealed that TNF-{alpha} induced activation of caspase 3 and Mst1 in a time- and dose-dependent manner. TNF-{alpha}-induced Mst1 activation is almost completely prevented by pretreatment with Z-DEVD-FMK, a caspase 3 inhibitor. Nuclear staining with Hoechst 33258 and fluorescence-activated cell sorting of propidium iodide-stained cells showed that TNF-{alpha} induced apoptosis of EC. Diphenyleneiodonium, an inhibitor of NADPH oxidase, and N-acetylcysteine, a potent antioxidant, also inhibited TNF-{alpha}-induced activation of Mst1 and caspase 3, as well as apoptosis. Knockdown of Mst1 expression by short interfering RNA attenuated TNF-{alpha}-induced apoptosis but not cleavage of caspase 3. These results suggest that Mst1 plays an important role in the induction of TNF-{alpha}-induced apoptosis of EC. However, positive feedback mechanism between Mst1 and caspase 3, which was shown in the previous studies, was not observed. Inhibition of Mst1 function may be beneficial for maintaining the endothelial integrity and inhibition of atherogenesis.

Ohtsubo, Hideki [Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka (Japan); Ichiki, Toshihiro [Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka (Japan)], E-mail: ichiki@cardiol.med.kyushu-u.ac.jp; Imayama, Ikuyo; Ono, Hiroki; Fukuyama, Kae; Hashiguchi, Yasuko [Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka (Japan); Sadoshima, Junichi [Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey (United States); Sunagawa, Kenji [Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka (Japan)

2008-03-07

61

ARID3B Induces Tumor Necrosis Factor Alpha Mediated Apoptosis While a Novel ARID3B Splice Form Does Not Induce Cell Death  

PubMed Central

Alternative splicing is a common occurrence in many cancers. Alternative splicing is linked with decreased apoptosis and chemoresistance in cancer cells. We previously demonstrated that ARID3B, a member of the AT-rich interactive domain (ARID) family of DNA binding proteins, is overexpressed in ovarian cancer. Therefore we wanted to assess the effect of ARID3B splice forms on cell viability. We identified a novel splice form of the ARID3B gene (designated as ARID3B Sh), which lacks the C-terminal exons 5–9 present in the full-length isoform (ARID3B Fl). ARID3B Fl is expressed in a variety of cancer cell lines. Expression of ARID3B Sh varied by cell type, but was highly expressed in most ovarian cancer lines. ARID3B is modestly transcriptionally activated by epidermal growth factor receptor (EGFR) signaling through the PEA3 transcription factor. We further found that ARID3B Fl is predominantly nuclear but is also present at the plasma membrane and in the cytosol. Endogenous ARID3B Sh is present in nuclear fractions, yet, when overexpressed ARID3B Sh accumulates in the cytosol and membrane fractions. The differential localization of these isoforms suggests they have different functions. Importantly, ARID3B Fl overexpression results in upregulation of pro-apoptotic BIM and induces Tumor Necrosis Factor alpha (TNF?) and TNF-related apoptosis inducing ligand (TRAIL) induced cell death. The ARID3B Fl-induced genes include TNF?, TRAIL, TRADD, TNF-R2, Caspase 10 and Caspase 7. Interestingly, ARID3B Sh does not induce apoptosis or expression of these genes. ARID3B Fl induces death receptor mediated apoptosis while the novel splice form ARID3B Sh does not induce cell death. Therefore alternative splice forms of ARID3B may play different roles in ovarian cancer progression.

Joseph, Stancy; Deneke, Victoria E.; Cowden Dahl, Karen D.

2012-01-01

62

Expression of neu protein, epidermal growth factor receptor, and transforming growth factor alpha in breast cancer. Correlation with clinicopathologic parameters.  

PubMed Central

The major objectives of this study were twofold: to determine 1) if growth factors or growth factor receptors were expressed similarly or differently in a clinically well-characterized group of breast cancer patients and 2) if these phenotypic characteristics were associated with any of the commonly used prognostic parameters. Formalin-fixed paraffin-embedded tumor tissue from 51 node-positive breast cancer patients were analyzed for the expression of neu, epidermal growth factor-receptor (EGF-R), and transforming growth factor alpha (TGF alpha) using immunoperoxidase staining. Positive membranous staining for neu was observed in 15 (29%) tumors. Over-expression of neu was observed in high-grade, estrogen-receptor-negative tumors (P less than 0.05). Epidermal growth factor receptor was expressed in 22 (43%) of the tumors analyzed and found to a greater degree in estrogen-receptor-negative and high-grade tumors (P less than 0.025). A significant correlation between neu and EGF-R expression was also noted. Tumors expressing membranous staining of neu had a greater than 70% chance of expressing EGF-R (P less than 0.01). Expression of TGF alpha was found in 68% of tumors and TGF alpha was detected in grade 1 and 2 tumor to a greater degree than EGF-R. The authors conclude that assaying tumors for these antigens may give additional phenotypic characteristics that can give further insight into the biology of breast cancer. Images Figure 1 Figure 2 Figure 3

Lundy, J.; Schuss, A.; Stanick, D.; McCormack, E. S.; Kramer, S.; Sorvillo, J. M.

1991-01-01

63

Fetal-derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand to induce smooth muscle cell death.  

PubMed

Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remodeled arteries but the mechanisms underlying this transformation remain unknown. This study investigated the hypothesis that fetal trophoblast invading from the placenta instigate remodeling by triggering cell death in vascular SMC. Specifically, a role for trophoblast-derived death inducing cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) was investigated. Expression of the activating TRAIL receptors R1 and R2 was detected by flow cytometry on human aortic SMC and by immunohistochemistry on spiral artery SMC. Recombinant human TRAIL induced human aortic SMC apoptosis, which was inhibited by antibodies against TRAIL-R1 or -R2. Perfusion of denuded spiral artery segments with recombinant human TRAIL also induced SMC apoptosis. Trophoblasts isolated from first trimester placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic SMC; apoptosis was significantly inhibited by a recombinant human TRAIL-R1:Fc construct. Trophoblast within the first trimester placental bed also expressed TRAIL. These data show that: 1) TRAIL causes SMC death; 2) trophoblast produce the apoptotic cytokine TRAIL; and 3) trophoblast induce SMC apoptosis via a TRAIL-dependent mechanism. We conclude that TRAIL produced by trophoblast causes apoptosis of SMC and thus may contribute to SMC loss during spiral artery remodeling in pregnancy. PMID:17322170

Keogh, Rosemary J; Harris, Lynda K; Freeman, Abigail; Baker, Philip N; Aplin, John D; Whitley, Guy StJ; Cartwright, Judith E

2007-02-22

64

Acute epithelial injury in the rat small intestine in vivo is associated with expanded expression of transforming growth factor alpha and beta.  

PubMed Central

BACKGROUND--Previous studies have shown the importance of transforming growth factors alpha and beta (TGF alpha and TGF beta) in modulating epithelial cell restitution after injury in vitro. AIM--To investigate the role of the growth factors TGF alpha and TGF beta after acute epithelial injury in vivo. METHODS--An in vivo model of phytohaemagglutinin (PHA) induced acute epithelial injury in rat small intestine was used. Epithelial cell turnover was assessed by autoradiography and liquid scintillation counting of thymidine uptake. Expression of TGF alpha and TGF beta was assessed by immunohistochemistry. RESULTS--An expansion of the proliferative compartment and increased turnover of intestinal epithelial cells was seen in rats with PHA induced intestinal epithelial injury. Expression of TGF alpha and TGF beta peptides was shown in both the epithelial cell and lamina propria compartment. Different patterns of TGF alpha and TGF beta expression were seen, however, within the epithelium of rats with acute intestinal injury compared with untreated controls, while the expression of these peptides within the lamina propria was not changed. CONCLUSIONS--These findings suggest that acute intestinal epithelial cell injury in vivo is associated with compensatory changes in expression of TGF alpha and TGF beta in the epithelial cell compartment, while the lamina propria does not seem to be significantly affected. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6

Dignass, A U; Stow, J L; Babyatsky, M W

1996-01-01

65

The promoting effect of tumour necrosis factor alpha in radiation-induced cell transformation.  

PubMed Central

The ability of tumour necrosis factor alpha (TNF-alpha), a potent endogenous inflammatory agent, to promote malignant transformation of Syrian hamster embryo cells (SHE) initiated by a 0.5-Gy dose of alpha-particles was investigated. Opsonized zymosan particles, which were phagocytosed by a human macrophage-like cell line, triggered TNF-alpha production from U937 cells. This cell supernatant could significantly increase the transformation frequency (TF) of primary SHE cells previously irradiated by a 0.5-Gy dose of alpha-particles. The TF decreased significantly if monoclonal antibody against TNF-alpha was added to the supernatant. Similarly, recombinant human TNF-alpha (rhTNF-alpha) increased the TF of alpha-irradiated primary SHE cells to an even greater extent. Addition of TNF-alpha to subcultures of irradiated SHE cells permitted the continuous propagation of these primary cells. In contrast, both TNF-alpha-treated control and alpha-irradiated cells without subsequent TNF-alpha treatment senesced after 7-15 passages. Irradiated SHE cells treated continuously with TNF-alpha could be subcultured over 40 passages and produced fibrosarcomas upon inoculation into nude mice. Our results provide the first evidence that TNF-alpha released by activated macrophages may contribute to the process of malignant transformation initiated by low-dose alpha-particles.

Guo, R. F.; Gong, Y. F.

1998-01-01

66

Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-alpha.  

PubMed

Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-alpha. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-kappaB and inhibited phosphorylation of inhibitor of kappa B (IkappaB) in TNF-alpha-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-alpha by inhibiting NF-kappaB-mediated iNOS expression and NO production and by preventing caspase-3 activation. PMID:19631208

Madonna, Rosalinda; Shelat, Harnath; Xue, Qun; Willerson, James T; De Caterina, Raffaele; Geng, Yong-Jian

2009-07-22

67

Expression of transforming growth factor-alpha in primary human colon and lung carcinomas.  

PubMed Central

The expression of TGF-alpha in human colon and lung carcinoma cell lines has been reported previously, but its expression in primary tumours has not been described in detail. We have used the radio-immunoassay method to measure the specific content of immunoreactive TGF-alpha in the acid ethanol extracts of normal and cancerous tissues of human colon and lung. The average TGF-alpha content of colon carcinomas is 4 times that of the normal mucosa, and for non-small cell lung carcinomas it is twice that of the normal parenchyma. Because of variability in the TGF-alpha expression among individuals and in different segments of colon and lobes of lung, the ratio of TGF-alpha content of paired tumour and normal tissue was also calculated. On average, the tumour/normal ratio for colon carcinoma is higher than that for lung carcinoma. Although 55% of colon tumours show a ratio 4 times, or greater, only 33% of lung carcinomas demonstrate this ratio. The level of TGF-alpha in both colon and lung carcinomas does not correlate with histological type stage, grade nor degree of desmoplasia of these tumours. Northern blot analysis of total cellular RNA confirms the expression of an approximately 4.8 kb TGF-alpha mRNA in normal colonic mucosa and lung parenchyma. However, in contrast to the results of radio-immunoassay, significant over-expression of TGF-alpha mRNA is uncommon in primary human colon carcinomas. Images Figure 3

Liu, C.; Woo, A.; Tsao, M. S.

1990-01-01

68

Transforming growth factor alpha attenuates the functional expression of AMPA receptors in cortical GABAergic neurons  

Microsoft Academic Search

In the developing neocortex, brain-derived neurotrophic factor (BDNF) exerts a trophic activity to increase the expression and channel activity of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor subunits. Here, we demonstrate that the epidermal growth factor (EGF) receptor (ErbB1) ligands exert the opposite biological activity in cultured neocortical neurons. Subchronic stimulation of ErbB1 with transforming growth factor ? (TGF?), EGF, or heparin-binding

Hisaaki Namba; Tadasato Nagano; Yuriko Iwakura; Huabao Xiong; Hussam Jourdi; Nobuyuki Takei; Hiroyuki Nawa

2006-01-01

69

Reduction of NO Synthase Expression and Tumor Necrosis Factor Alpha Production in Macrophages by Amphotericin B Lipid Carriers  

PubMed Central

The present study compared the abilities of different lipid carriers of amphotericin B (AMB) to activate murine peritoneal macrophages, as assessed by their capacities to produce nitric oxide (NO) and tumor necrosis factor alpha (TNF-?). Although AMB alone did not induce NO production, synergy was observed with gamma interferon but not with lipopolysaccharide. This synergy could not be explained by the mobilization of the nuclear activation factor NF-?B by AMB. On the other hand, AMB induced TNF-? production without a costimulator and no synergy was observed. Anti-TNF-? antibodies did not influence NO production, and an inhibitor of NO synthase did not affect TNF-? production, indicating that the production of one of these effector molecules was independent of that of the other. The incorporation of AMB into lipid carriers reduced NO and TNF-? production with all formulations but more so with liposomes than with lipid complexes. NO production was correlated with the induction of NO synthase II, revealed by Western blotting. The extent of association of AMB with macrophages depended on the formulation, especially on the AMB/lipids ratio: the higher the ratio was, the greater the AMB association with macrophages. However, there was no clear correlation between AMB association with macrophages, whether internalized or bound to the membrane, and immunostimulating effects. These results may explain the reduced toxicities of lipid-based formulations of AMB.

Larabi, Malika; Legrand, Philippe; Appel, Martine; Gil, Sophie; Lepoivre, Michel; Devissaguet, Jean-Philippe; Puisieux, Francis; Barratt, Gillian

2001-01-01

70

Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa.  

PubMed

Hidradenitis suppurativa is a chronic skin condition, characterized clinically by painful, recurrent, deep- seated nodules and suppuration, and histologically by hyper-trophic scarring of apocrine gland bearing skin and sinus tracts. The overall consequence of the disease is considerable tissue remodelling and the underlying alterations in innate immunity are poorly understood. The aim of this study was to evaluate the expression of human beta-defensin 2, tumour necrosis factor (TNF)-? and matrix metalloproteinase-2 in skin lesions of patients with hidradenitis suppurativa. A total of 14 skin samples from patients and 2 skin samples from healthy volunteers were evaluated by immunohistochemistry. Human beta-defensin 2 was negative in 12/14 specimens. Elevated expression of metalloproteinase-2 was observed in keratinocytes, fibroblasts and inflammatory cells in dermis, sweat glands, hair follicles and sinus tracts, suggesting a key role for hidradenitis suppurativa pathogenesis. Decreased human beta-defensin 2 in the presence of inflammatory (TNF-?-containing) cells suggests a decreased innate immunity in hidradenitis suppurativa-affected skin. PMID:23096596

Mozeika, Elga; Pilmane, Mara; Nürnberg, Birgit Meinecke; Jemec, Gregor B E

2013-05-01

71

The roles of tumor necrosis factor-alpha in colon tight junction protein expression and intestinal mucosa structure in a mouse model of acute liver failure  

Microsoft Academic Search

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common clinical disease and one of the most severe complications of acute liver failure (ALF). Although the mechanism responsible for SBP is unclear, cytokines play an important role. The aim of this study was to investigate the effects of tumor necrosis factor-alpha (TNF-?) on the structure of the intestinal mucosa and the expression

Hong-Li Song; Sa Lv; Pei Liu

2009-01-01

72

p70 S6 kinase limits tumor necrosis factor-alpha-induced interleukin-6 synthesis in osteoblast-like cells.  

PubMed

Our previous study demonstrated that tumor necrosis factor-alpha (TNF-alpha) stimulates the synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, via p44/p42 mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase/Akt in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether p70 S6 kinase is involved in TNF-alpha-stimulated IL-6 synthesis in MC3T3-E1 cells. TNF-alpha time dependently induced the phosphorylation of p70 S6 kinase. Rapamycin, an inhibitor of p70 S6 kinase, which attenuated the phosphorylation of p70 S6 kinase induced by TNF-alpha, significantly amplified the TNF-alpha-stimulated IL-6 synthesis. TNF-alpha-induced phosphorylations of both p44/p42 MAP kinase and Akt were markedly enhanced by rapamycin. The amplification by rapamycin of TNF-alpha-induced IL-6 synthesis was reduced by PD98059, a specific inhibitor of MEK1/2, or Akt inhibitor. Rapamycin enhanced the IL-6 synthesis and the phosphorylation of Akt induced by TNF-alpha also in human osteoblasts. Taken together, these results strongly suggest that p70 S6 kinase limits the TNF-alpha-stimulated IL-6 synthesis at a point upstream from p44/p42 MAP kinase and Akt in osteoblast-like cells. PMID:19879324

Minamitani, Chiho; Tokuda, Haruhiko; Adachi, Seiji; Matsushima-Nishiwaki, Rie; Yamauchi, Junichi; Kato, Kenji; Natsume, Hideo; Mizutani, Jun; Kozawa, Osamu; Otsuka, Takanobu

2009-10-29

73

Effect of tumor necrosis factor-alpha on acyl coenzyme A: cholesteryl acyltransferase activity and ACAT1 gene expression in THP-1 macrophages.  

PubMed

In order to explore the effect and mechanisms of tumor necrosis factor-alpha (TNF-alpha) on the activity of the acyl coenzyme A: cholesteryl acyltransferase (ACAT), THP-1 monocytes were cultured and induced to differentiate into macrophages with phorbol ester. TNF-alpha (60 ng/mL) was added at different time points into the macrophage-containing medium and the ACAT enzyme activity was measured by quantifying the incorporation of [1-(14)C] oleoyl CoA into cholesteryl esters. The expression of ACAT-1 protein and mRNA was respectively detected by Western blotting and RT-PCR in THP-1 macrophages 24 h after treatment with TNF-alpha (60 ng/mL). The results indicated that ACAT activity in THP-1 macrophages treated with TNF-alpha was increased in a time-dependent manner. The expression levels of ACAT-1 protein and mRNA were significantly increased in THP-1 macrophages after treatment with TNF-alpha (P<0.05). It was suggested that TNF-alpha could increase the activity of ACAT in THP-1 macrophages by up-regulating the expression of ACAT-1 gene. PMID:17497288

He, Ping; Cheng, Bei; Wang, Yi; Wang, Hongxing

2007-04-01

74

Expression of transforming growth factor alpha mRNA in benign and malignant tissues derived from gynecologic patients with various proliferative conditions.  

PubMed

Growth factors are polypeptides involved in the regulation of normal and malignant cell growth. Transforming growth factor alpha (TGF alpha) is one of such protein growth factors that plays an important role in the regulation of mammalian cell growth. In this study, the expression of TGF alpha mRNA was studied in tissue specimens obtained at the time of surgery from patients with benign and malignant gynecologic proliferative conditions. To analyze TGF alpha mRNA expression we utilized the highly sensitive technique denoted Message Amplification Phenotyping which can detect mRNA in single cells. This technique consists of isolating RNA, reverse transcription of total cellular RNA to produce copy DNA, followed by enzymatic amplification of TGF alpha cDNA fragments using specific TGF alpha primers and polymerase chain reaction. The results showed significant levels to TGF alpha mRNA expression in vulvar (100% of the cases positive), cervical (66% positive), and endometrial (66% positive) carcinomas. Moreover, vulvar condylomas produced by human papilloma virus (HPV) showed the highest levels of TGF alpha mRNA expression of all the pathological tissues examined. In contrast, vulvar melanoma, fibrocystic disease of the breast, and certain ovarian tumors showed undetectable TGF alpha mRNA expression. Normal mesodermal tissues such as myometrium, abdominal rectus muscle, and fallopian tubes were negative for TGF alpha mRNA expression. However, TGF alpha mRNA was present in normal cervix and in normal endometrium. The results showed that TGF alpha mRNA expression is frequently associated with various malignant tumors and HPV-induced lesions of epithelial origin, suggesting that TGF alpha mRNA protein product may be a contributory factor in the progression of these pathological tissue alterations. Finally, TGF alpha mRNA expression was not restricted to malignant cells, suggesting that the TGF alpha mRNA protein product may function as a mitogen in the normal human epithelial tissues examined. PMID:1323947

Xynos, F P; Klos, D J; Hamilton, P D; Schuette, V; Fernandez-Pol, J A

75

Microcystin-LR induces endoplasmatic reticulum stress and leads to induction of NF?B, interferon-alpha, and tumor necrosis factor-alpha.  

PubMed

Microcystins (MCs) are hepatotoxins produced by cyanobacteria responsible for toxicity in humans and animals. Here, we investigate unexplored molecular pathways by which microcystin-LR (MC-LR) acts on hepatocytes to elucidate unknown modes of action. We focus on the endoplasmatic reticulum (ER) stress response or unfolded protein response (UPR), and on mechanisms that may contribute to the tumor-promoting effect of MCs in animals, including the activation of NF?B, the expression of interferon alpha (IFN-?) and the induction of interferon stimulated genes (ISGs), as well as the expression of tumor necrosis factor alpha (TNF-?). To this end, we exposed human hepatoma cells (Huh7) to 0.5 ?M (nontoxic concentration), 5 ?M (EC50 concentration), 25 ?M and 50 ?M (cytotoxic concentrations) MC-LR for 6, 24, 48, and 72 h. The expression of phosphatase 2A (PP2A) mRNA and protein was induced at 5 ?M MC-LR. Phosphorylated P-CREB, a transcription factor for PP2A, leads to elevated expression of PP2A. Furthermore, all of the three ER stress pathways, the UPR and the endoplasmic reticulum-associated degradation were activated after exposure to 5, 25, and 50 ?M MC-LR. Additionally, the expression of NF?B, IFN-?, and several INF-?-stimulated genes was strongly activated. The proinflammatory cytokine TNF-? was also induced. Our data demonstrate that MC-LR induces all ER stress response pathways. Consequently NF?B is activated, which in turn induces the expression of IFN-? and TNF-?. All of these activated pathways, which are analyzed here for the first time in detail, may contribute to the hepatotoxic, inflammatory, and tumorigenic action of MC-LR. PMID:23431999

Christen, Verena; Meili, Nicole; Fent, Karl

2013-03-07

76

Inhibition of Tumor Necrosis Factor Alpha by an Adenovirus-Encoded Soluble Fusion Protein Extends Transgene Expression in the Liver and Lung  

Microsoft Academic Search

The cellular and humoral immune responses to adenovirus (Ad) remain a major barrier to Ad-mediated gene therapy. We recently reported that mice deficient in tumor necrosis factor alpha (TNF-a) or Fas (APO-1, CD95) have prolonged expression of an Ad transgene expressing a foreign protein in the liver. To determine whether blockade of TNF-a or Fas would have the same effect

YUFENG PENG; JOSE TREVEJO; JUNLIANG ZHOU; MICHAEL W. MARINO; RONALD G. CRYSTAL; ERIK FALCK-PEDERSEN; KEITH B. ELKON

1999-01-01

77

Mycobacterium avium subsp. paratuberculosis infection causes suppression of RANTES, monocyte chemoattractant protein 1, and tumor necrosis factor alpha expression in peripheral blood of experimentally infected cattle.  

PubMed

Blood from cattle with subclinical Mycobacterium avium subsp. paratuberculosis infection was stimulated with M. avium subsp. paratuberculosis antigens, and expression of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), RANTES, monocyte chemoattractant protein 1 (MCP-1), and IL-8 was measured. Expression of TNF-alpha, RANTES, and MCP-1 was lower in infected than in uninfected cattle. The reduced response may weaken protective immunity and perpetuate infection. PMID:14638822

Buza, Joram J; Mori, Yasuyuki; Bari, Abusaleh M; Hikono, Hirokazu; Aodon-geril; Hirayama, Sachiyo; Shu, Yujing; Momotani, Eiichi

2003-12-01

78

Mycobacterium avium subsp. paratuberculosis Infection Causes Suppression of RANTES, Monocyte Chemoattractant Protein 1, and Tumor Necrosis Factor Alpha Expression in Peripheral Blood of Experimentally Infected Cattle  

PubMed Central

Blood from cattle with subclinical Mycobacterium avium subsp. paratuberculosis infection was stimulated with M. avium subsp. paratuberculosis antigens, and expression of interleukin-1? (IL-1?), tumor necrosis factor alpha (TNF-?), RANTES, monocyte chemoattractant protein 1 (MCP-1), and IL-8 was measured. Expression of TNF-?, RANTES, and MCP-1 was lower in infected than in uninfected cattle. The reduced response may weaken protective immunity and perpetuate infection.

Buza, Joram J.; Mori, Yasuyuki; Bari, Abusaleh M.; Hikono Aodon-geril, Hirokazu; Hirayama, Sachiyo; Shu, Yujing; Momotani, Eiichi

2003-01-01

79

Lipoteichoic Acids from Lactobacillus Strains Elicit Strong Tumor Necrosis Factor Alpha-Inducing Activities in Macrophages through Toll-Like Receptor 2  

Microsoft Academic Search

Lactobacilli are nonpathogenic gram-positive inhabitants of microflora. At least some Lactobacillus strains have been postulated to have health beneficial effects, such as the stimulation of the immune system. Here we examined the stimulatory effects of lactobacilli on mouse immune cells. All six heat-killed Lactobacillus strains examined induced the secretion of tumor necrosis factor alpha (TNF-) from mouse splenic mononuclear cells,

Tetsuya Matsuguchi; Akimitsu Takagi; Takeshi Matsuzaki; Masato Nagaoka; Kimika Ishikawa; Teruo Yokokura; Yasunobu Yoshikai

2003-01-01

80

DNA damage induced by tumour necrosis factor-alpha in L929 cells is mediated by mitochondrial oxygen radical formation.  

PubMed Central

Treatment of L929 cells with tumour necrosis factor-alpha (TNF-alpha) plus actinomycin D induced DNA damage (indicated by the appearance of a sub-G1 peak due to extracellular leakage of low molecular weight DNA following DNA fragmentation) before significant cell lysis occurred. The DNA damage occurred in parallel with a decrease of the intracellular total glutathione content and an increase of intracellular reactive oxygen intermediates (ROI), as indicated by increased dihydrorhodamine 123 oxidation. Because the inhibition of mitochondrial respiration suppressed the increase of dihydrorhodamine 123 oxidation and DNA damage as well as the decrease in the total glutathione content, it was suggested that increased mitochondrial formation of ROI was responsible for DNA damage after TNF treatment. Deferoxamine (a ferric iron chelator) and dithiothreitol (a sulfhydryl reagent) both prevented DNA damage and cell killing, indicate that hydroxyl radicals generated from O2- and H2O2 produced by the mitochondria in a process catalysed by iron contributed to DNA damage and that this pathway may be involved in TNF-alpha-induced cytotoxicity. An inhibitor of poly(ADP)-ribose polymerase (3-aminobenzamide), worsened DNA damage, but was protective against cell lysis, suggesting that DNA repair subsequent to injury was more important than DNA damage per se in development of TNF-alpha cytotoxicity.

Shoji, Y; Uedono, Y; Ishikura, H; Takeyama, N; Tanaka, T

1995-01-01

81

Tumor necrosis factor-alpha-induced apoptosis in hepatocytes in long-term culture.  

PubMed Central

Apoptosis occurs naturally in the liver and increases in specific pathogenic processes. We previously described the use of a chemically defined medium supplemented with epidermal growth factor and dimethylsulfoxide to maintain rat hepatocytes in a highly differentiated state for more than 30 days (long-term culture). In this study, we showed that hepatocytes in long-term dimethylsulfoxide culture have definite advantages over using cells in short-term culture (cells in culture for 2 to 4 days) to study apoptosis. We demonstrated that treatment with tumor necrosis factor (TNF)-alpha induced apoptosis (detected morphologically and by formation of an oligonucleosomal DNA ladder) only in hepatocytes that had been subjected to dimethylsulfoxide removal. Neither treatment with TNF-alpha alone or dimethylsulfoxide removal alone induced apoptosis. Apoptosis could be induced by concentrations as low as 500 U of TNF-alpha/ml. Although a DNA ladder was not detected by 12 hours after TNF-alpha treatment, it was easily identified by 24 hours. We conclude that this system can be used 1) to examine the underlying mechanism by which TNF-alpha causes apoptosis in hepatocytes and 2) to study induction of apoptosis in hepatocytes by other agents. Images Figure 1 Figure 2 Figure 3 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9

Bour, E. S.; Ward, L. K.; Cornman, G. A.; Isom, H. C.

1996-01-01

82

Protein kinase C-dependent phosphorylation is involved in resistance to tumour necrosis factor-alpha-induced cytotoxicity in a human monocytoid cell line.  

PubMed Central

To investigate the mechanism underlying resistance to tumour necrosis factor-alpha (TNF alpha)-induced cytotoxicity, we have developed a human hybrid cell line, designated A10, derived from the fusion of human U-937 monocytoid cells and human monocytes, which expressed large numbers of TNF alpha receptors and yet remained highly resistant to TNF alpha. However, in the presence of the protein kinase C (PKC) inhibitors RO-31-7549 or RO-31-8220 (donated by Roche), these cells became sensitive to TNF alpha-induced cytotoxicity, suggesting that PKC activity is required for protective mechanisms. On investigation of protein phosphorylation in TNF alpha-stimulated permeabilized A10 cells, a rapid increase in serine/threonine phosphorylation of phosphoproteins of molecular masses 130, 90, 80, 65 and 42 kDa was found. Subsequently, we found a similar pattern of increased phosphorylation following stimulation of A10 cells with mezerein, a phorbol ester derivative which activates PKC, a serine/threonine kinase. The theory that activation of PKC was responsible for increased phosphorylation was confirmed by a dose-dependent inhibition of the TNF alpha-induced protein phosphorylation by the PKC inhibitors RO-31-7549 and RO-31-8220. The possible link between the TNF alpha-stimulated early protein phosphorylation events and the maintenance of protective mechanisms against TNF alpha-induced cytotoxicity is discussed. Images Figure 3

Sampson, L E; Mire-Sluis, A; Meager, A

1993-01-01

83

Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.  

PubMed

Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-alpha (TNFalpha) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91(phox), the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type, iNOS-/-, and gp91(phox-/-) mice. TNFalpha neutralizing antibody inhibited LPS toxicity, and addition of TNFalpha induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNFalpha or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNFalpha signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death. PMID:18480288

Li, Jianrong; Ramenaden, E Radhika; Peng, Jie; Koito, Hisami; Volpe, Joseph J; Rosenberg, Paul A

2008-05-14

84

Tumor necrosis factor alpha induces Warburg-like metabolism and is reversed by anti-inflammatory curcumin in breast epithelial cells.  

PubMed

The reprogramming of cellular metabolism in cancer cells is a well-documented effect. It has previously been shown that common oncogene expression can induce aerobic glycolysis in cancer cells. However, the direct effect of an inflammatory microenvironment on cancer cell metabolism is not known. Here, we illustrate that treatment of nonmalignant (MCF-10a) and malignant (MCF-7) breast epithelial cells with low-level (10 ng/ml) tumor necrosis factor alpha (TNF-?) significantly increased glycolytic reliance, lactate export and expression of the glucose transporter 1 (GLUT1). TNF-? decreased total mitochondrial content; however, oxygen consumption rate was not significantly altered, suggesting that overall mitochondrial function was increased. Upon glucose starvation, MCF7 cells treated with TNF-? demonstrated significantly lower viability than nontreated cells. Interestingly, these properties can be partially reversed by coincubation with the anti-inflammatory agent curcumin in a dose-dependent manner. This work demonstrates that aerobic glycolysis can be directly induced by an inflammatory microenvironment independent of additional genetic mutations and signals from adjacent cells. Furthermore, we have identified that a natural dietary compound can reverse this effect. PMID:23661584

Vaughan, Roger A; Garcia-Smith, Randi; Dorsey, Jonathan; Griffith, Jeffrey K; Bisoffi, Marco; Trujillo, Kristina A

2013-06-10

85

Amiodarone Exposure During Modest Inflammation Induces Idiosyncrasy-like Liver Injury in Rats: Role of Tumor Necrosis Factor-alpha  

PubMed Central

Amiodarone [2-butyl-3-(3?,5?-diiodo-4’?-diethylaminoethoxybenzoyl)-benzofuran] (AMD), a class III antiarrhythmic drug, is known to cause idiosyncratic hepatotoxic reactions in human patients. One hypothesis for the etiology of idiosyncratic adverse drug reactions is that a concurrent inflammatory stress results in decreased threshold for drug toxicity. To explore this hypothesis in an animal model, male Sprague-Dawley rats were treated with nonhepatotoxic doses of AMD or its vehicle and with saline vehicle or lipopolysaccharide (LPS) to induce low-level inflammation. Elevated alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase activities as well as increased total bile acid concentrations in serum and midzonal hepatocellular necrosis were observed only in AMD/LPS-cotreated rats. The time interval between AMD and LPS administration was critical: AMD injected 16 h before LPS led to liver injury, whereas AMD injected 2–12 h before LPS failed to cause this response. The increase in ALT activity in AMD/LPS cotreatment showed a clear dose-response relationship with AMD as well as LPS. The metabolism and hepatic accumulation of AMD were not affected by LPS coexposure. Serum concentration of tumor necrosis factor-alpha (TNF) was significantly increased by LPS and was slightly prolonged by AMD. In Hepac1c7 cells, addition of TNF potentiated the cytotoxicity of both AMD and its primary metabolite, mono-N-desethylamiodarone. In vivo inhibition of TNF signaling by etanercept attenuated the AMD/LPS-induced liver injury in rats. In summary, AMD treatment during modest inflammation induced severe hepatotoxicity in rats, and TNF contributed to the induction of liver injury in this animal model of idiosyncratic AMD-induced liver injury.

Lu, Jingtao; Jones, A. Daniel; Harkema, Jack R.; Roth, Robert A.; Ganey, Patricia E.

2012-01-01

86

Potentiation of tumor necrosis factor-alpha-induced tumor cell apoptosis by a small molecule inhibitor for anti-apoptotic protein hPEBP4.  

PubMed

hPEBP4 (human phosphatidylethanolamine-binding protein 4) has been identified to be able to potentiate the resistance of breast, prostate, and ovarian cancers, with the preferential expression of hPEBP4, to tumor necrosis factor-alpha (TNF-alpha) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, suggesting that inhibitors targeting the anti-apoptotic protein hPEBP4 may be useful to increase the sensitivity of hPEBP4-expressing cancer cells to TNF-alpha or TRAIL-induced apoptosis. By structure-based virtual screening and following surface plasmon resonance-based binding assay, seven small compounds were found to potently bind with hPEBP4. The hit compounds were further functionally screened for their ability to inhibit cancer cell growth, and one small compound, IOI-42, was identified to be able to promote TNF-alpha-mediated growth inhibition of MCF-7 breast cancer cells. IOI-42 could potentiate TNF-alpha-induced apoptosis of MCF-7 cells by inhibiting hPEBP4 and could suppress anchorage-independent cell growth of MCF-7 cells. We further demonstrated that IOI-42 could reduce the endogenous association of hPEBP4 with Raf-1/MEK1 and enhance the activation of ERK1/2 and JNK while inhibiting Akt activation. Furthermore, IOI-42 also promoted TRAIL-induced cell apoptosis of prostate cancer cells. Taken together, our data suggest that IOI-42, as the first chemical inhibitor of anti-apoptotic protein hPEBP4, may serve as a potential anti-tumor drug by sensitizing tumor cells to apoptotic inducers. PMID:20177075

Qiu, Jianming; Xiao, Jianfeng; Han, Chaofeng; Li, Nan; Shen, Xu; Jiang, Hualiang; Cao, Xuetao

2010-02-22

87

The roles of tumor necrosis factor-alpha in colon tight junction protein expression and intestinal mucosa structure in a mouse model of acute liver failure  

PubMed Central

Background Spontaneous bacterial peritonitis (SBP) is a common clinical disease and one of the most severe complications of acute liver failure (ALF). Although the mechanism responsible for SBP is unclear, cytokines play an important role. The aim of this study was to investigate the effects of tumor necrosis factor-alpha (TNF-?) on the structure of the intestinal mucosa and the expression of tight junction (Zona Occludens 1; ZO-1) protein in a mouse model of ALF. Methods We induced ALF using D-galactosamine/lipopolysaccharide (GalN/LPS) or GalN/TNF-? and assessed the results using transmission electron microscopy, immunohistochemistry, Western blotting, ELISA and real-time quantitative PCR. The effects of administration of anti-TNF-? IgG antibody or anti-TNF-? R1 antibody before administration of GalN/LPS or GalN/TNF-?, respectively, on TNF-? were also assessed. Results Morphological abnormalities in the intestinal mucosa of ALF mice were positively correlated with serum TNF-? level. Electron microscopic analysis revealed tight junction (TJ) disruptions, epithelial cell swelling, and atrophy of intestinal villi. Gut bacteria invaded the body at sites where TJ disruptions occurred. Expression of ZO-1 mRNA was significantly decreased in both ALF models, as was the level of ZO-1 protein. Prophylactic treatment with either anti-TNF-? IgG antibody or anti-tumor necrosis factor-a receptor1 (anti-TNF-? R1) antibody prevented changes in intestinal tissue ultrastructure and ZO-1 expression. Conclusion TNF-? affects the structure of the intestinal mucosa, decreases expression of ZO-1, and affects the morphology of the colon in a mouse model of ALF. It also may participate in the pathophysiological mechanism of SBP complicated to ALF.

2009-01-01

88

The role of nitric oxide in cardiac depression induced by interleukin-1 beta and tumour necrosis factor-alpha.  

PubMed Central

1. Myocardial dysfunction during septic shock is associated with enhanced production of cytokines such as interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). These cytokines depress cardiac mechanical function by a mechanism which is not well defined. 2. Bacterial endotoxin or cytokines cause the expression of Ca(2+)-independent nitric oxide (NO) synthase in cardiac myocytes, vascular endothelial cells and endocardial endothelial cells, causing enhanced production of NO. As NO has negative inotropic actions on cardiac muscle, we tested the sum effects of IL-1 beta plus TNF-alpha in the intact heart to determine whether enhanced expression of NO synthase activity in the cells that comprise the heart is involved in cardiac depression associated with cytokine stimulation. 3. Rat isolated working hearts perfused with IL-1 beta plus TNF-alpha showed a markedly greater depression in contractile function, measured as cardiac work, after 2 h of perfusion compared with time-matched control hearts. The depressant action of IL-1 beta plus TNF-alpha was first apparent after 1 h of perfusion; no early (15 min) cardiac depressant actions were seen. 4. The competitive inhibitor of Ca(2+)-dependent and Ca(2+)-independent NO synthases, NG-nitro-L-arginine methyl ester (L-NAME, 3 microM) when given concurrently with IL-1 beta plus TNF-alpha prevented the loss in contractile function such that these hearts after 2 h of perfusion had similar function to time-matched controls. L-NAME did not acutely reverse the loss of contractile function in hearts exposed for 2 h to IL-1 beta plus TNF-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Schulz, R; Panas, D L; Catena, R; Moncada, S; Olley, P M; Lopaschuk, G D

1995-01-01

89

Protein kinase C synergistically stimulates tumor necrosis factor-alpha-induced secretion of urokinase-type plasminogen activator in human dental pulp cells.  

PubMed

Plasminogen activator (PA) is the enzyme converting plasminogen to its active form, plasmin, involved in various physiological and pathological phenomena. The conversion is catalyzed by two types of PA, urokinase-type PA (uPA) and tissue-type PA (tPA). When human dental pulp cells were stimulated by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), PA activity in the conditioned medium was increased, indicating that TNF-alpha provoked PA secretion. The TNF-alpha-induced PA release was significantly enhanced in the presence of phorbol-12-myristate-13-acetate (PMA), a protein kinase C (PKC) activator. The PKC inhibitor Ro31-8220 abolished the effect of PMA on the PA release. The activity of PA secreted from the cells stimulated by TNF-alpha and PMA was reduced by immunoprecipitation using anti-uPA antibody. PMA failed to enhance the TNF-alpha-induced expression of uPA mRNA. These results suggest that protein kinase C synergistically enhances the secretion of uPA in TNF-alpha-stimulated human dental pulp cells. PMID:18177545

Hashizume, Hideki; Kamio, Naoto; Nakao, Sumi; Matsushima, Kiyoshi; Sugiya, Hiroshi

2008-01-08

90

Beneficial Dysregulation of the Time Course of Inflammatory Mediators in Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Factor-Deficient Mice?  

PubMed Central

To begin to understand the surprising survival of macrophage-specific lipopolysaccharide-induced tumor necrosis factor alpha factor-deficient (macLITAF?/?) animals after a lethal dose of lipopolysaccharide (LPS), as reported earlier, the present follow-up study focuses on the role of LITAF in the regulation of inflammatory cytokines secreted in response to lethal or sublethal doses of LPS administered to wild-type (WT) and macLITAF?/? mice. A time course study of kinase expression in peritoneal macrophages revealed increased phosphorylation of prosurvival kinases Akt, Erk1/2, and ribosomal S6 kinase (RSK) in macLITAF?/? mice compared to that in WT mice (n = 8), confirming their role in LPS-mediated diseases. macLITAF?/? mice (n = 8) survived a lethal dose of LPS plus d-galactosamine (d-GalN), expressing lower serum levels of pro- and anti-inflammatory cytokines than the WT levels. To extend our knowledge on LPS-induced inflammatory events, an effective sublethal dose of LPS was administered to the animals (n = 14). WT animals exhibited an acute inflammatory response that decreased after 4 h. Interestingly, macLITAF?/? mice exhibited an initial delay in the secretion of proinflammatory cytokines that peaked after 8 h and reached WT levels after 18 h. Anti-inflammatory cytokine secretions were initially delayed but increased after 4 h and remained elevated compared to WT levels, even after 18 h. Our results demonstrate that LITAF deficiency in vivo affects cytokines other than TNF-? and influences the balance between the pro- and anti-inflammatory cytokines, which protects the animals from the deleterious effects of an LPS-induced inflammatory response, resulting in a beneficial host regulation of inflammatory cytokines and in enhanced survival. Therapeutic intervention aimed at reducing LITAF via kinase modulators may prove useful in preventing LPS-induced mortality.

Srinivasan, Sreedevi; Leeman, Susan E.; Amar, Salomon

2010-01-01

91

Beneficial dysregulation of the time course of inflammatory mediators in lipopolysaccharide-induced tumor necrosis factor alpha factor-deficient mice.  

PubMed

To begin to understand the surprising survival of macrophage-specific lipopolysaccharide-induced tumor necrosis factor alpha factor-deficient (macLITAF(-/-)) animals after a lethal dose of lipopolysaccharide (LPS), as reported earlier, the present follow-up study focuses on the role of LITAF in the regulation of inflammatory cytokines secreted in response to lethal or sublethal doses of LPS administered to wild-type (WT) and macLITAF(-/-) mice. A time course study of kinase expression in peritoneal macrophages revealed increased phosphorylation of prosurvival kinases Akt, Erk1/2, and ribosomal S6 kinase (RSK) in macLITAF(-/-) mice compared to that in WT mice (n = 8), confirming their role in LPS-mediated diseases. macLITAF(-/-) mice (n = 8) survived a lethal dose of LPS plus d-galactosamine (d-GalN), expressing lower serum levels of pro- and anti-inflammatory cytokines than the WT levels. To extend our knowledge on LPS-induced inflammatory events, an effective sublethal dose of LPS was administered to the animals (n = 14). WT animals exhibited an acute inflammatory response that decreased after 4 h. Interestingly, macLITAF(-/-) mice exhibited an initial delay in the secretion of proinflammatory cytokines that peaked after 8 h and reached WT levels after 18 h. Anti-inflammatory cytokine secretions were initially delayed but increased after 4 h and remained elevated compared to WT levels, even after 18 h. Our results demonstrate that LITAF deficiency in vivo affects cytokines other than TNF-alpha and influences the balance between the pro- and anti-inflammatory cytokines, which protects the animals from the deleterious effects of an LPS-induced inflammatory response, resulting in a beneficial host regulation of inflammatory cytokines and in enhanced survival. Therapeutic intervention aimed at reducing LITAF via kinase modulators may prove useful in preventing LPS-induced mortality. PMID:20219876

Srinivasan, Sreedevi; Leeman, Susan E; Amar, Salomon

2010-03-10

92

Cell-type-specific expression of the platelet-derived growth factor alpha receptor: a role for GATA-binding protein.  

PubMed Central

Platelet-derived growth factor alpha receptor (PDGF alpha R) is a transmembrane tyrosine kinase receptor for all three existing PDGF isoforms, AA, AB, and BB. Transcripts of PDGF alpha R are detected as early as in fertilized mouse eggs and throughout adulthood in a time- and space-specific manner, thereby suggesting an important role of PDGFs in mammalian development. In this study, we have investigated the mechanism involved in cell-type-specific PDGF alpha R gene expression during early embryonic development. Using F9 embryonic carcinoma cells as an in vitro study model, we identified a differentiation-dependent enhancer element within the PDGF alpha R promoter that controlled receptor expression during parietal endoderm cell differentiation induced by retinoic acid and dibutyryl cyclic AMP treatment. The differentiation-dependent enhancer element sequence bore no resemblance to consensus DNA-binding sites of either the retinoic acid receptor family or the cyclic AMP-responsive element-binding protein family. It was composed of two identical 12-bp direct repeats separated by a 17-bp insert sequence enriched in C and A nucleotides. Although only a single repeat was needed to form specific DNA-protein complexes with factors present in F9 parietal endoderm cell extracts, both repeats together were necessary to display cell-type-specific enhancing activity. Mutational analysis revealed that the protein-binding sites within the repeat sequences were identical to GATA-binding sites. In this study, we provided evidence to suggest that a member of the GATA transcription factor family (GATA-4) is responsible for parietal endoderm-specific PDGF alpha R expression.

Wang, C; Song, B

1996-01-01

93

Gene Expression and Production of Tumor Necrosis Factor Alpha, Interleukin1beta (IL1beta ), IL8, Macrophage Inflammatory Protein 1alpha (MIP1alpha ), MIP1beta , and Gamma Interferon-Inducible Protein 10 by Human Neutrophils Stimulated with Group B Meningococcal Outer Membrane Vesicles  

Microsoft Academic Search

Accumulation of polymorphonuclear neutrophils (PMN) into the subarachnoidal space is one of the hall- marks of Neisseria meningitidis infection. In this study, we evaluated the ability of outer membrane vesicles (OMV) from N. meningitidis B to stimulate cytokine production by neutrophils. We found that PMN stimulated in vitro by OMV produce proinflammatory cytokines and chemokines including tumor necrosis factor alpha

JOSÉ A. LAPINET; PATRIZIA SCAPINI; FEDERICA CALZETTI; O. Perez; MARCO A. CASSATELLA

2000-01-01

94

Apical effect of diosmectite on damage to the intestinal barrier induced by basal tumour necrosis factor-alpha.  

PubMed Central

BACKGROUND: In many digestive diseases the intestinal barrier is weakened by the release of proinflammatory cytokines, including tumour necrosis factor-alpha (TNF alpha). AIM: To investigate the protective effect of apical diosmectite on the intestinal dysfunction induced by the proinflammatory cytokine TNF alpha. METHODS: Filter grown monolayers of the intestinal cell line HT29-19A were incubated for 48 hours in basal medium containing 10 ng/ml TNF alpha and 5 U/ml interferon-gamma (IFN gamma). Next, 1, 10, or 100 mg/ml diosmectite was placed in the apical medium for one hour. Intestinal function was then assessed in Ussing chambers by measuring ionic conductance (G) and apicobasal fluxes of 14C-mannitol (Jman), and intact horseradish peroxidase. In control intestinal monolayers, diosmectite did not significantly modify G, Jman, or intact horseradish peroxidase. RESULTS: After incubation with TNF alpha and IFN gamma, intestinal function altered, as shown by the increases compared with control values for G (22.8 (3.7) v (9.6 (0.5) mS/cm2), Jman (33.8 (7.5) v 7.56 (0.67) micrograms/h x cm2), and intact horseradish peroxidase (1.95 (1.12) v 0.14 (0.04) micrograms/h x cm2). G and Jman were closely correlated, suggesting that the increase in permeability was paracellular. Treatment with diosmectite restored al the variables to control values. CONCLUSIONS: Basal TNF alpha disrupts the intestinal barrier through the tight junctions, and apical diosmectite counteracts this disruption.

Mahraoui, L; Heyman, M; Plique, O; Droy-Lefaix, M T; Desjeux, J F

1997-01-01

95

Identification of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) and its receptors in adult rat ventral prostate.  

PubMed

Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor-alpha (TNF-alpha) family of cytokines that is known to induce apoptosis upon binding to its death domain-containing receptors, DR4/TRAIL-R1 and DR5/TRAIL-R2. Two additional TRAIL receptors, DcR1/TRAIL-R3 and DcR2/TRAIL-R4, lack functional death domains and act as decoy receptors for TRAIL. In this study, the presence of TRAIL and its receptors was investigated in adult rat hormonosensitive ventral prostate. TRAIL and its receptors were identified in the rat ventral prostate in terms of protein and mRNA. TRAIL and its receptors were immunolocalized in prostatic epithelial cells. PMID:12573821

Vindrieux, David; Devonec, Marian; Benahmed, Mohamed; Grataroli, Renée

2002-12-30

96

Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients  

Microsoft Academic Search

Cytokines have been implicated in the pathogenesis of the euthyroid sick syndrome. Isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rTNF) and melphalan in patients with melanoma or sarcoma is accompanied by high systemic TNF levels. We examined the prolonged effects (7 days) of ILP on thyroid hormone metabolism with respect to induction and recovery of the

R. A. Feelders; A. J. G. Swaak; J. A. Romijn; A. M. M. Eggermont; E. T. Tielens; G. Vreugdenhill; E. Endert; H. G. van Eijk; A. Berghout

1999-01-01

97

Interferon-gamma sensitizes the human salivary gland cell line, HSG, to tumor necrosis factor-alpha induced activation of dual apoptotic pathways  

Microsoft Academic Search

Activated immune cells secrete proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interferon–gamma\\u000a (IFN-gamma) and Fas ligand (FasL) and these cytokines have been reported to induce apoptosis in numerous cell types. Apoptotic\\u000a cell death has been associated with the progression of numerous autoimmune diseases. Proinflammatory cytokines are reportedly\\u000a involved in apoptosis in the salivary glands of patients with Sjögren’s

Kashmira Kulkarni; Kaisa Selesniemi; Thomas L. Brown

2006-01-01

98

Dermal tumour necrosis factor-alpha induces dendritic cell migration to draining lymph nodes, and possibly provides one stimulus for Langerhans' cell migration.  

PubMed Central

Previous studies have shown that following skin sensitization there is an accumulation of dendritic cells (DC) in lymph nodes draining the site of exposure. A significant number of the DC which arrive in the lymph nodes bear high levels of antigen, and the available evidence indicates that they are derived from epidermal Langerhans' cells (LC). Although freshly isolated LC are relatively inefficient antigen-presenting cells, the antigen-bearing DC which are found within draining nodes following skin sensitization are highly immunostimulatory. Recent investigations indicate that the functional maturation of LC as they migrate from the skin is reflected by an enhanced capacity to form stable clusters with lymphocytes, and is associated with an increased expression of membrane major histocompatibility complex (MHC) class II (Ia) antigen. By analogy with in vitro studies of LC maturation, it is possible that such changes are effected by granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin-1 (IL-1), both of which are products of epidermal cells. The question remains as to the nature of the stimulus that initiates LC migration. In the present study we have examined in mice the effects of intradermal injection of tumour necrosis factor-alpha (TNF-alpha), another epidermal cytokine, on the accumulation of DC in lymph nodes. Murine recombinant TNF-alpha was found to cause a concentration- and time-dependent increase in the number of DC within draining nodes. Under the same conditions of exposure murine recombinant GM-CSF was without effect. Heat treatment of mouse TNF-alpha resulted in an equivalent inhibition of both DC accumulation and cytotoxic activity measured by in vitro bioassay. An interesting observation was that equal concentrations of human TNF-alpha, of equivalent specific activity, failed to influence the frequency of lymph node DC. These data demonstrate that TNF-alpha induces DC accumulation in draining lymph nodes, and we propose that this cytokine may provide one stimulus for LC migration during cutaneous immune responses.

Cumberbatch, M; Kimber, I

1992-01-01

99

Cathepsin B inhibition improves lung injury associated to d -galactosamine\\/tumor necrosis factor-alpha-induced liver injury in mice  

Microsoft Academic Search

The present study was designed to investigate the effects of benzyloxicarbonyl-l-phenylalanyl-alanine-fluoromethylketone (Z-FA.FMK), an inhibitor of cathepsin B on lung injury that occurs concurrently with\\u000a liver injury induced by d-galactosamine\\/tumor necrosis factor-alpha (d-GalN\\/TNF-?). Four groups of BALB\\/c male mice were treated as follows: Group 1—mice receiving intravenous (iv) injections\\u000a of physiological saline; Group 2—administered with 8 mg\\/kg Z-FA.FMK by iv injection; Group

Fusun Oztay; Selda Gezginci-Oktayoglu; Bertan Boran Bayrak; Refiye Yanardag; Sehnaz Bolkent

2010-01-01

100

MicroRNA-23a modulates tumor necrosis factor-alpha-induced osteoblasts apoptosis by directly targeting fas.  

PubMed

Tumor necrosis factor (TNF)-alpha is a key cytokine regulator of bone and mediates inflammatory bone loss. The molecular signaling that regulates bone loss downstream of TNF-alpha is poorly defined. Recent studies implicated an important role of microRNAs (miRNAs) in TNF-alpha-mediated bone metabolism, including osteoblasts differentiation, osteoclasts differentiation and apoptosis. However, there are very few studies on the complex regulation of miRNAs during TNF-alpha-induced osteoblasts apoptosis. In the present study, the clonal murine osteoblastic cell line, MC3T3-E1, was used. We screened for differentially expressed miRNAs during TNF-alpha induced MC3T3-E1 cell apoptosis and identified microRNA-23a as a potential inhibitor of apoptosis. To delineate the role of microRNA-23a in apoptosis, we respectively silenced and overexpressed microRNA-23a in MC3T3-E1 cells. We found that microRNA-23a depletion significantly enhances TNF-alpha-induced MC3T3-E1 cell apoptosis and over-expressing microRNA-23a remarkably attenuates this phenomenon. Mechanistic studies showed that microRNA-23a inhibits Fas expression through a microRNA-23a-binding site within the 3'-untranslational region of Fas. The post-transcriptional repression of Fas was further confirmed by luciferase reporter assay. These results showed that microRNA-23a, an important protecting factor, plays a significant role in the process of TNF-alpha induced MC3T3-E1 cell apoptosis, by regulating Fas expression. J. Cell. Biochem. 114: 2738-2745, 2013. © 2013 Wiley Periodicals, Inc. PMID:23804233

Dong, Jun; Cui, Xingang; Jiang, Zhensong; Sun, Jianmin

2013-12-01

101

Effect of megestrol acetate on weight loss induced by tumour necrosis factor alpha and a cachexia-inducing tumour (MAC16) in NMRI mice.  

PubMed Central

The effect of the synthetic progesterone, megestrol acetate, on weight loss induced by both tumour necrosis factor alpha (TNF) as a model for the cachexia accompanying the acquired immunodeficiency syndrome and by a cachexia-inducing tumour (MAC16) has been studied in NMRI mice. Megestrol acetate was effective in preventing weight loss in both model systems with treated animals having an increase in intake of both food and water. Megestrol acetate was unable to prevent loss of body weight in animals pair-fed with TNF treated animals, suggesting that the increase in food and water intake was responsible for the increase in body weight. Analysis of body composition showed that the major contribution to the increase in body weight in animals treated with megestrol acetate was an increase in water content, although there was also an increase in carcass fat in animals bearing the MAC16 tumour given the high dose of megestrol acetate. Animals bearing the MAC16 tumour had a significant increase in tumour weight after treatment with megestrol acetate, possibly owing to the increased plasma glucose levels. These results suggest that an increase in appetite and weight gain alone are not sufficient to justify the anticachectic effect of a particular agent and that body composition analysis and tumour growth rate are very important parameters.

Beck, S. A.; Tisdale, M. J.

1990-01-01

102

Ricin induces the production of tumour necrosis factor-alpha and interleukin-1 beta by human peripheral-blood mononuclear cells.  

PubMed Central

Ricin induced the release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta by human peripheral-blood mononuclear cells in a dose- and time-dependent manner. The inhibition induced by ricin upon the phytohaemagglutinin (PHA)-driven lymphocyte proliferation was greater in cultures of mononuclear cells than that observed in monocyte-free cultures of lymphocytes, and was decreased after addition of an anti-TNF-alpha antibody to PHA-activated cultures. Low levels of TNF-alpha were detected in plasma from rats poisoned with ricin. These results suggest that ricin induced the release of macrophage-derived cytokines which may have a role in the pathogenesis of ricin toxic effects.

Licastro, F; Morini, M C; Bolognesi, A; Stirpe, F

1993-01-01

103

Expressions of Tumor Necrosis Factor Alpha and MicroRNA-155 in Immature Rat Model of Status Epilepticus and Children with Mesial Temporal Lobe Epilepsy.  

PubMed

Recently, the role of inflammation has attracted great attention in the pathogenesis of mesial temporal lobe epilepsy (MTLE), and microRNAs start to emerge as promising new players in MTLE pathogenesis. In this study, we investigated the dynamic expression patterns of tumor necrosis factor alpha (TNF-?) and microRNA-155 (miR-155) in the hippocampi of an immature rat model of status epilepticus (SE) and children with MTLE. The expressions of TNF-? and miR-155 were significantly upregulated in the seizure-related acute and chronic stages of MTLE in the immature rat model and also in children with MTLE. Modulation of TNF-? expression, either by stimulation using myeloid-related protein (MRP8) or lipopolysaccharide or inhibition using lenalidomide on astrocytes, leads to similar dynamic changes in miR-155 expression. Our study is the first to focus on the dynamic expression pattern of miR-155 in the immature rat of SE lithium-pilocarpine model and children with MTLE and to detect their relationship at the astrocyte level. TNF-? and miR-155, having similar expression patterns in the three stages of MTLE development, and their relationship at the astrocyte level may suggest a direct interactive relationship during MTLE development. Therefore, modulation of the TNF-?/miR-155 axis may be a novel therapeutic target for the treatment of MTLE. PMID:23636891

Ashhab, Muhammad Usman; Omran, Ahmed; Kong, Huimin; Gan, Na; He, Fang; Peng, Jing; Yin, Fei

2013-05-01

104

Integrin expression by human epidermal keratinocytes can be modulated by interferon-gamma, transforming growth factor-beta, tumor necrosis factor-alpha, and culture on a dermal equivalent.  

PubMed

Receptors of the integrin family are largely confined to the basal layer of keratinocytes, both in human epidermis and in stratified cultures of human keratinocytes. However, suprabasal integrin expression is observed during epidermal wound healing and in psoriatic lesions. We have investigated potential stimuli of suprabasal expression. Addition of transforming growth factor-beta (TGF-beta), interferon-gamma (IFN-gamma), or tumor necrosis factor-alpha (TNF-alpha) to keratinocytes cultured with a 3T3 feeder layer did not induce suprabasal expression. The cytokines caused small changes in the levels of alpha 2 beta 1 or alpha 3 beta 1 on the surface of basal keratinocytes but had no significant effect on the proportion of cells adhering to fibronectin, type IV collagen, and laminin, and did not cause changes in the mobility of integrin subunits on polyacrylamide gels. Injection of TNF-alpha or IFN-gamma intradermally into healthy human volunteers induced an inflammatory response but did not induce suprabasal integrin expression. However, we did observe transient suprabasal integrin expression when keratinocytes were grown on a dermal equivalent consisting of fibroblasts in a collagen gel. One week after raising the cultures to the air-liquid interface, beta 1 integrins were found in all the viable cell layers, with suprabasal cells co-expressing integrins and involucrin; 1 week later integrins were confined to the basal layer. Addition of TGF-beta, IFN-gamma, or TNF-alpha to the dermal equivalents neither induced nor inhibited suprabasal integrin expression. We conclude that suprabasal integrin expression is not induced by the inflammatory cytokines tested, and instead may reflect the proliferation/differentiation status of the epidermis. PMID:7829883

Hertle, M D; Jones, P H; Groves, R W; Hudson, D L; Watt, F M

1995-02-01

105

Potentiation by tumour necrosis factor-alpha of calcium signals induced by bradykinin and carbachol in human tracheal smooth muscle cells.  

PubMed Central

The effect of tumour necrosis factor-alpha (TNF alpha) on the increase in cytosolic free calcium ([Ca2+])i induced by carbachol and bradykinin (BK) was investigated in human tracheal smooth muscle cells in culture (TSMC). BK (10(-12)-10(-9) M) and carbachol (10(-7)-10(-3) M) produced a concentration-dependent increase in [Ca2+]i (pD2 = 10.73 +/- 0.05 and 5.57 +/- 0.03 respectively). The increase in [Ca2+]i was significantly enhanced for both agonists in TNF alpha-treated cells (10 ng ml-1 for 24 h). However, pD2 values were not modified (10.78 +/- 0.03 and 5.62 +/- 0.04 for BK and carbachol, respectively) suggesting that no change in the apparent receptor affinity occurred. Thus, TNF alpha induced-alterations in Ca2+ homeostasis in human TSMC may be a key mechanism underlying airway hyperreactivity.

Amrani, Y; Martinet, N; Bronner, C

1995-01-01

106

Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain  

PubMed Central

Although microglia are the only cells found to be productively infected in the central nervous system of acquired immunodeficiency disease syndrome (AIDS) patients, there is extensive white and gray matter disease nonetheless. This neuropathogenesis is believed to be due to indirect mechanisms other than infection with human immunodeficiency virus 1 (HIV-1). Cytokines and toxic small molecules have been implicated in the clinical and histopathological findings in CNS AIDS. Previously, we have demonstrated in rodent glial cultures the presence of biologically active epitopes of gp120 and gp41 that are capable of inducing interleukin 1 and tumor necrosis factor alpha. In this study, we map the HIV-1 envelope epitopes that induce nitric oxide, inducible nitric oxide synthase, interleukin 1, and tumor necrosis factor alpha in human glial cultures. Epitopes in the carboxy terminus of gp120 and the amino terminus of gp41 induce these proinflammatory entities. In addition, we compare HIV-1 infection and pathology in glial cells derived from human brain taken at different states of maturation (fetal, neonatal, and adult brain) in an effort to address some of the clinical and histological differences seen in vivo. This study demonstrates that, in the absence of virus infection and even in the absence of distinct viral tropism, human glia respond like rodent glia to non-CD4-binding epitopes of gp120/gp41 with cytokine and nitric oxide production. Differences among fetal, neonatal, and adult glial cells' infectivity and cytokine production indicate that, in addition to functional differences of glia at different stages of development, cofactors in vitro and in vivo may also be critical in facilitating the biological responses of these cells to HIV-1.

1995-01-01

107

Role of hypoxia-inducible factor-{alpha} in hepatitis-B-virus X protein-mediated MDR1 activation  

SciTech Connect

The transition from chemotherapy-responsive cancer cells to chemotherapy-resistant cancer cells is mainly accompanied by the increased expression of multi-drug resistance 1 (MDR1). We found that hepatitis-B-virus X protein (HBx) increases the transcriptional activity and protein level of MDR1 in a hepatoma cell line, H4IIE. In addition, HBx overexpression made H4IIE cells more resistant to verapamil-uptake. HBx stabilized hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) and induced the nuclear translocation of C/EBP{beta}. Reporter gene analyses showed that HBx increased the reporter activity in the cells transfected with the reporter containing MDR1 gene promoter. Moreover, the luciferase reporter gene activity was significantly inhibited by HIF-1{alpha} siRNA but not by overexpression of C/EBP dominant negative mutant. These results imply that HBx increases the MDR1 transporter activity through the transcriptional activation of the MDR1 gene with HIF-1{alpha} activation, and suggest HIF-1{alpha} for the therapeutic target of HBV-mediated chemoresistance.

Han, Hyo-Kyung [BK21 Project Team, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea (Korea, Republic of); Han, Chang Yeob [BK21 Project Team, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea (Korea, Republic of); Cheon, Eun-Pa [BK21 Project Team, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea (Korea, Republic of); Lee, Jaewon [College of Pharmacy, Pusan National University, Busan 609-735, South Korea (Korea, Republic of); Kang, Keon Wook [BK21 Project Team, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea (Korea, Republic of)]. E-mail: kwkang@chosun.ac.kr

2007-06-01

108

Platelet-derived growth factor alpha receptor gene expression: isolation and characterization of the promoter and upstream regulatory elements.  

PubMed Central

Receptors for the platelet-derived growth factors (PDGFs) are expressed conditionally in developing embryos and adult tissues. Aberrant expression of PDGF receptors is a molecular marker for proliferative disorders such as atherosclerosis, myofibrosis, and malignant astrocytoma. We isolated genomic clones that encompass the 5' end of the mouse PDGF alpha receptor mRNA transcript and extend 10 kb into the upstream flanking region of the gene. Using these clones, we constructed a partial genomic map that locates the promoter and transcription start sites of the gene. One of our genomic clones contains cis-acting regulatory elements that drive expression of reporter gene constructs selectively in cells that express PDGF alpha receptors. Images

Wang, C; Stiles, C D

1994-01-01

109

Prognostic role of myocardial tumor necrosis factor-alpha and terminal complement complex expression in patients with dilated cardiomyopathy  

Microsoft Academic Search

Background: In patients with dilated cardiomyopathy (DCM), elevated plasma levels of tumor necrosis factor-a (TNF-a) are associated with poor prognosis. The terminal complement complex (C5b-9) stimulates myocardial TNF-a expression. Aims: To investigate whether myocardial TNF-a and C5b-9 expression correlate with clinical outcome in DCM. Methods and results: 71 patients with DCM underwent myocardial biopsy. Biopsies were analyzed for TNF-a, C5b-9,

Oliver Zimmermann; Matthias Kochs; Thomas P. Zwaka; Magdalena Bienek-Ziolkowski; Martin Hoher; Vinzenz Hombach; Jan Torzewski

110

Tumour Necrosis Factor Alpha, Interferon Gamma and Substance P Are Novel Modulators of Extrapituitary Prolactin Expression in Human Skin  

PubMed Central

Human scalp skin and hair follicles (HFs) are extra-pituitary sources of prolactin (PRL). However, the intracutaneous regulation of PRL remains poorly understood. Therefore we investigated whether well-recognized regulators of pituitary PRL expression, which also impact on human skin physiology and pathology, regulate expression of PRL and its receptor (PRLR) in situ. This was studied in serum-free organ cultures of microdissected human scalp HFs and skin, i.e. excluding pituitary, neural and vascular inputs. Prolactin expression was confirmed at the gene and protein level in human truncal skin, where its expression significantly increased (p?=?0.049) during organ culture. There was, however, no evidence of PRL secretion into the culture medium as measured by ELISA. PRL immunoreactivity (IR) in female human epidermis was decreased by substance P (p?=?0.009), while neither the classical pituitary PRL inhibitor, dopamine, nor corticotropin-releasing hormone significantly modulated PRL IR in HFs or skin respectively. Interferon (IFN) ? increased PRL IR in the epithelium of human HFs (p?=?0.044) while tumour necrosis factor (TNF) ? decreased both PRL and PRLR IR. This study identifies substance P, TNF? and IFN? as novel modulators of PRL and PRLR expression in human skin, and suggests that intracutaneous PRL expression is not under dopaminergic control. Given the importance of PRL in human hair growth regulation and its possible role in the pathogenesis of several common skin diseases, targeting intracutaneous PRL production via these newly identified regulatory pathways may point towards novel therapeutic options for inflammatory dermatoses.

Langan, Ewan A.; Vidali, Silvia; Pigat, Natascha; Funk, Wolfgang; Lisztes, Erika; Biro, Tamas; Goffin, Vincent; Griffiths, Christopher E. M.; Paus, Ralf

2013-01-01

111

Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes.  

PubMed

This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins. PMID:1922031

Musgrove, E A; Lee, C S; Sutherland, R L

1991-10-01

112

Herpes simplex virus type 2-induced mortality following genital infection is blocked by anti-tumor necrosis factor alpha antibody in CXCL10-deficient mice.  

PubMed

The role of tumor necrosis factor alpha (TNF-alpha) was evaluated for CXCL10-deficient (CXCL10(-/-)) mice which succumbed to genital herpes simplex virus type 2 (HSV-2) infection and possessed elevated levels of virus and TNF-alpha but not other cytokines in the central nervous system (CNS) and vaginal tissue within the first 7 days following virus exposure. Anti-TNF-alpha but not control antibody treatment offsets the elevated mortality rate of CXCL10(-/-) mice, despite increased CNS viral titers. In addition, TNF-alpha neutralization suppressed recruitment of leukocyte subpopulations into the CNS, which is associated with reduced CCL2 and CXCL9 expression. Collectively, the results implicate TNF-alpha as the principal mediator of mortality in response to genital HSV-2 infection. PMID:18684827

Thapa, Manoj; Carr, Daniel J J

2008-08-06

113

The presence of periodontopathogens associated with the tumour necrosis factor-alpha expression in patients with different periodontal status.  

PubMed

The purpose of this study was to investigate the relationship between P gingivalis, T forsythia, T denticola, P intermedia, and A. actinomycetemcomitans in the sulci or pockets of patients with gingivitis (G), mild chronic periodontitis (MiCP), moderate chronic periodontitis (MoCP) and severe periodontitis (SP), and the expression of TNF-alpha in gingival tissue associated with clinical parameters. Six patients with G, 7 with MiCP, 23 with MoCP and 7 with SP were recruited. Pathogens obtained from the sulci or pockets were identified by PCR, and expression of TNF-alpha from gingival tissue was analysed Probing depth (PD), clinical attachment level (CAL) and loss of bone were recorded. P gingivalis was detected at the following rates: 16.6% in subjects with G 57.1% in MiCP 57.8 % in MoCP and 58.1% in SP (p < 0.05). P intermedia was not identified in subjects with G A. actinomycetemcomitans was only identified in subjects with MoCP (31.5%) and SP (42.8%). T denticola and T forsythia were identified in all subject groups. Bacterial combinations were identified as follows: P denticola + P intermedia and PR intermedia + T forsythia were associated (p = 0.04, p = 0.02) with the presence of TNF-alpha mRNA in 20% and 25% of subjects, respectively. P gingivalis + A. Actinomycetemcomitans andA. actinomycetemcomitans + T forsythia were associated with severe PD and CAL, respectively. The association between the presence of P intermedia and expression levels of TNF-alpha was significant (p = 0.05). These results indicate that the proportion of patients with P gingivalis increases with the progression of disease. We observed that the presence of P intermedia may trigger the expression of TNF-alpha and cause a worsening of the patient's clinical status. PMID:22928386

Monetti, Marina; Usin, María M; Tabares, Sandra; Gonzalez, Analía; Cabral, Humberto R A; Sembaj, Adela

2012-01-01

114

Molecular cloning and expression analysis of sea bass (Dicentrarchus labrax L.) tumor necrosis factor-alpha (TNF-alpha).  

PubMed

In the search for pro-inflammatory genes in sea bass a TNF-alpha gene was cloned and sequenced. The sea bass TNF-alpha (sbTNF-alpha) putative protein conserves the TNF-alpha family signature, as well as the two cysteines usually involved in the formation of a disulfide bond. The mouse TNF-alpha Thr-Leu cleavage sequence and a potential transmembrane domain were also found, suggesting that sbTNF-alpha exists as two forms: a approximately 28 kDa membrane-bound form and a approximately 18.4 kDa soluble protein. The single copy sbTNF-alpha gene contains a four exon-three intron structure similar to other known TNF-alpha genes. Homology modeling of sbTNF-alpha is compatible with the trimeric quaternary architecture of its mammalian counterparts. SbTNF-alpha is constitutively expressed in several unstimulated tissues, and was not up-regulated in the spleen and head-kidney, in response to UV-killed Photobacterium damselae subsp. piscicida. However, an increase of sbTNF-alpha expression was detected in the head-kidney during an experimental infection using the same pathogen. PMID:17433716

Nascimento, Diana S; Pereira, Pedro J B; Reis, Marta I R; do Vale, Ana; Zou, Jun; Silva, Manuel T; Secombes, Christopher J; dos Santos, Nuno M S

2007-02-24

115

Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-alpha converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma.  

PubMed

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-alpha, was inhibited by TNF-alpha protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G2-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process. PMID:16982746

Ringel, Jörg; Jesnowski, Ralf; Moniaux, Nicolas; Lüttges, Jutta; Ringel, Jens; Choudhury, Amit; Batra, Surinder K; Klöppel, Günter; Löhr, Matthias

2006-09-15

116

Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophoblast apoptosis in a Toll-like receptor-2 and tumour necrosis factor-alpha dependent manner.  

PubMed

Placentae obtained from newborns with congenital human cytomegalovirus (HCMV) infection often display chronic villitis and disruptions of the syncytiotrophoblast (ST). Little is known about how HCMV infection induces inflammation in the villous placenta and loss of the trophoblast. We propose that the inflammation is initiated with innate defence responses of the ST to maternal blood-borne virus. In this paper we show with a culture model (ST derived from primary cytotrophoblasts) that UV-inactivated HCMV (UV-HCMV) doubled the frequency of ST apoptosis. ST cultures challenged with UV-HCMV increased transcription and secretion of the inflammatory cytokines tumour necrosis factor alpha (TNFalpha) and interleukin-8, and antibody to TNFalpha inhibited UV-HCMV-induced apoptosis. Treatment with cycloheximide, an inhibitor of protein translation, did not reduce UV-HCMV-induced TNFalpha gene transcription, indicating that upregulation was independent of de novo protein synthesis. Neutralizing antibody to Toll-like receptor (TLR)2 inhibited UV-HCMV-induced transcription and translation of TNFalpha, and consequently inhibited the increase in ST apoptosis. Our results show that even transcriptionally inactive HCMV binding to TLR2 on ST can initiate inflammation, including secretion of TNFalpha, which leads to trophoblast death. PMID:16826536

Chan, G; Guilbert, L J

2006-09-01

117

Fatty Acids Isolated from Toxoplasma gondii Reduce Glycosylphosphatidylinositol-Induced Tumor Necrosis Factor Alpha Production through Inhibition of the NF-?B Signaling Pathway?  

PubMed Central

Glycosylphosphatidylinositols (GPIs) are involved in the pathogenicity of protozoan parasites and are known to induce inflammatory cytokines. However, we have previously shown that the family of six GPIs of Toxoplasma gondii extracted together from tachyzoites could not induce tumor necrosis factor alpha (TNF-?) secretion by macrophages, whereas GPIs individually separated from this extract by thin-layer chromatography (TLC) were able to stimulate the cells. In the present study we show that the TLC step makes it possible to eliminate inhibitors extracted together with the T. gondii GPIs. Among the non-GPI molecules we have isolated fatty acids able to inhibit the secretion of TNF-? induced by the T. gondii GPIs. Myristic and palmitic acids reduce the production of TNF-? through the inhibition of tyrosine phosphorylation of cytoplasmic proteins and the inhibition of NF-?B activation in a peroxisome proliferator-activated receptor-independent pathway and after a rapid entry into the cytoplasm of macrophages. GPIs are considered toxins inducing irreversible damage in the host, and fatty acids produced in parallel by the parasite could reduce the immune response, thus favoring the persistence of parasite infection.

Debierre-Grockiego, Francoise; Rabi, Khamran; Schmidt, Jorg; Geyer, Hildegard; Geyer, Rudolf; Schwarz, Ralph T.

2007-01-01

118

In vitro effects of tumor necrosis factor-alpha on human thyroid follicular cells.  

PubMed

Tumor necrosis factor-alpha is assumed to be an important mediator in thyroid autoimmunity. In the present study we have shown that human thyrocytes possess a single specific binding site for recombinant tumor necrosis factor-alpha with an average of 9,300 receptors/cell (Kd = 1.9 x 10(-10) mol). The effects of the cytokine on thyroid cell proliferation were assessed by 3H-thymidine uptake as well as by the protein and DNA content of cell monolayers. Low dose tumor necrosis factor-alpha resulted in a moderate stimulation of cell proliferation with an increase of 3H-thymidine incorporation from 44,613 +/- 7,989 cpm under basal conditions to 63,326 +/- 6,822 cpm after 100 U/l tumor necrosis factor-alpha (p < 0.01). Higher doses of the cytokine were less effective. On average, bTSH stimulated cAMP production of human thyrocytes was significantly augmented after preincubation with recombinant tumor necrosis factor-alpha. The maximum effect was observed after 1,000 U/l tumor necrosis factor-alpha (281.5 +/- 107.0 vs 114.5 +/- 33.6 fmol cAMP/micrograms protein under basal conditions: p < 0.05), whereas higher doses of the cytokine were again less effective. This phenomenon could at least partly be explained by a cytokine-mediated downregulation of tumor necrosis factor-alpha binding. We conclude that in vitro tumor necrosis factor-alpha modulates in addition to its well known synergistic effect on interferon-gamma induced HLA class II expression the function and proliferation of human thyroid follicular cells as well. These effects are mediated via specific cell surface receptors. PMID:1329418

Deuss, U; Buscema, M; Schumacher, H; Winkelmann, W

1992-09-01

119

The receptor for interleukin 3 is selectively induced in human endothelial cells by tumor necrosis factor alpha and potentiates interleukin 8 secretion and neutrophil transmigration.  

PubMed

Interleukin (IL)-3 stimulates hemopoiesis in vitro. However, IL-3 is not normally found in bone marrow, raising doubts as to the in vivo role of IL-3. We have found that human umbilical vein endothelial cells (HUVEC) express functional high-affinity receptors for IL-3 after stimulation with tumor necrosis factor alpha (TNF-alpha), IL-1 beta, or lipopolysaccharide, and that this receptor is involved in inflammatory phenomena. TNF-alpha caused time- and dose-dependent up-regulation of mRNA for the IL-3 receptor alpha and beta chains, with maximal effects occurring 16-36 h after stimulation with TNF-alpha at 100 units/ml. Induction of mRNA correlated with protein expression on the cell surface as judged by monoclonal antibody staining and by the ability of HUVEC to specifically bind 125I-labeled IL-3. Scatchard analysis under optimal conditions of TNF-alpha stimulation revealed approximately 1500 IL-3 receptors per cell, which were of a high-affinity class (Kd = 500 pM) only. In contrast to a previous report, receptors for granulocyte-macrophage colony-stimulating factor could not be detected. IL-3 binding to TNF-alpha-activated HUVEC enhanced IL-8 production, E-selection expression, and neutrophil transmigration. The selective induction of a functional IL-3 receptor on endothelial cells suggests that, beyond hemopoiesis, IL-3 may have an important role in chronic inflammation and in allergic diseases. PMID:7504295

Korpelainen, E I; Gamble, J R; Smith, W B; Goodall, G J; Qiyu, S; Woodcock, J M; Dottore, M; Vadas, M A; Lopez, A F

1993-12-01

120

Effect of Gastrodia elata on tumor necrosis factor-alpha-induced matrix metalloproteinase activity in endothelial cells  

Microsoft Academic Search

The aim of the present study was to investigate whether an ethanol extract of Gastrodia elata (EGE) rhizome, a traditional Korean herbal medical food, suppresses the endothelial extracellular matrix degradation induced\\u000a by tumor necrosis factor (TNF)-?. Gelatin zymography results showed that pretreatment with EGE to human umbilical vein endothelial\\u000a cells (HUVEC) decreased TNF-?-induced increase of matrix metalloproteinase (MMP)-2\\/-9 activities in

Yun Jung Lee; Sun Mi Hwang; Dae Gill Kang; Jin Sook Kim; Ho Sub Lee

2009-01-01

121

Tumor necrosis factor alpha-induced phosphorylation of I kappa B alpha is a signal for its degradation but not dissociation from NF-kappa B.  

PubMed Central

Activation of the NF-kappa B/Rel family of transcription factors is regulated by a cytoplasmic inhibitor, I kappa B alpha. Activity of I kappa B alpha is in turn modulated by phosphorylation and proteolysis. It has been postulated that phosphorylation of I kappa B alpha leads to its dissociation from NF-kappa B, and free I kappa B alpha is targeted for rapid degradation. However, this phosphorylation-mediated dissociation event has not been demonstrated in vivo. We demonstrate that, contrary to this hypothesis, phosphorylation of I kappa B alpha induced by tumor necrosis factor alpha in HeLa cells does not induce dissociation. We propose a model in which (i) induced phosphorylation of I kappa B alpha does not result in its dissociation from NF-kappa B, (ii) phosphorylation of I kappa B alpha serves as a signal for degradation, and (iii) degradation of I kappa B alpha occurs while it is still complexed with NF-kappa B. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5

Miyamoto, S; Maki, M; Schmitt, M J; Hatanaka, M; Verma, I M

1994-01-01

122

Infection of Human Fallopian Tube Epithelial Cells with Neisseria gonorrhoeae Protects Cells from Tumor Necrosis Factor Alpha-Induced Apoptosis  

Microsoft Academic Search

Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection

Priscilla Morales; Paz Reyes; Macarena Vargas; Miguel Rios; Monica Imarai; Hugo Cardenas; Horacio Croxatto; Pedro Orihuela; Renato Vargas; Juan Fuhrer; John E. Heckels; Myron Christodoulides; Luis Velasquez

2006-01-01

123

Two types of tumor necrosis factor-alpha in bluefin tuna (Thunnus orientalis) genes: Molecular cloning and expression profile in response to several immunological stimulants.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) is a key inflammatory mediator and has also the potential as a prominent biomarker of innate immunity. In this study, we identified and characterized TNF-alpha from bluefin tuna, which is an important cultured species. Two types of TNF-alpha were also cloned incidentally (TNF1 and TNF2). The open reading frame of TNF1 and TNF2 cDNA encoded 247 and 245 amino acids, respectively. The amino acid sequence identity among sea perch, red sea bream, and tiger puffer was 73, 70, 59% for TNF1 and 49, 51, 45% for TNF2, respectively. The identity between TNF1 and TNF2 amino acid sequences of the bluefin tuna was only 43%. The positions of cysteine residues, transmembrane sequence, and protease cleavage site in bluefin tuna TNFs were similar with other reported fish and mammalian TNF-alpha. In a phylogenetic analysis, TNF1 is grouped with other reported Perciformes TNF-alpha. On the other hand, TNF2 is grouped with ayu TNF and is quite distant from the fish TNF-alpha group and lymphotoxin-beta group. While TNF1 mRNA showed no significant difference in all tissues, TNF2 mRNA was expressed significantly higher in the blood than in the gill, intestine, head kidney, spleen, heart, and ovary. In peripheral blood leucocytes (PBL), expressions of TNF2 mRNA were significantly increased by stimulation with lipopolysaccharide, phytohemagglutinin, concanavalin A, pokeweed mitogen, phorbol myristate acetate in vitro, but those of TNF1 were not. Recombinant mature TNF1 and TNF2 proteins significantly enhanced phagocytic activity of PBL. Our results suggest that bluefin tuna possess two types of TNF-alpha homologue, and TNF2 is a potential biomarker for innate immunity. PMID:19146959

Kadowaki, Takeshi; Harada, Hideaki; Sawada, Yoshifumi; Kohchi, Chie; Soma, Gen-Ichiro; Takahashi, Yukinori; Inagawa, Hiroyuki

2008-12-31

124

ROLES OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF-A) IN MEDIATION OF DIOXIN (TCDD)-INDUCED DELAYS IN DEVELOPMENT OF THE MOUSE MAMMARY GLAND  

EPA Science Inventory

Roles of Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGF-a) in Mediation of Dioxin (TCDD)-Induced Delays in Development of the Mouse Mammary Gland. Suzanne E. Fenton, Barbara Abbott, Lamont Bryant, and Angela Buckalew. U.S. EPA, NHEERL, Reproductive Tox...

125

Medicinal foodstuffs. XXIX. Potent protective effects of sesquiterpenes and curcumin from Zedoariae Rhizoma on liver injury induced by D-galactosamine/lipopolysaccharide or tumor necrosis factor-alpha.  

PubMed

The 80% aqueous acetone extract of Zedoariae Rhizoma was found to show a protective effect against D-galactosamine (D-GalN)/lipopolysaccharide-induced acute liver injury in mice. To clarify the active compounds, the principal constituents were examined and 11 sesquiterpenes (furanodiene, curdione, neocurdrione, dehydrocurdione, germacrone, 13-hydroxygermacrone, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone) and a diarylheptanoid (curcumin) were found to inhibit the increase in serum aspartate aminotransaminase and alanine aminotransaminase at a dose of 50 mg/kg p.o. in agreement with the previous in vitro studies, except for dehydrocurdione, aerugidiol, and zedoarondiol. In particular, curdione, neocurdione, curcumenol, and isocurcumenol potently inhibited the increase at a dose of 12.5 mg/kg p.o. Furthermore, the eight sesquiterpenes, furanodiene, curdione, neocurdione, dehydrocurdione, germacrone, 13-hydroxygermacrone, curcumenol, and curcumenone, also showed a protective effect against D-GalN/tumor necrosis factor-alpha-induced liver injury in mice at a dose of 50 mg/kg p.o. PMID:12033504

Morikawa, Toshio; Matsuda, Hisashi; Ninomiya, Kiyofumi; Yoshikawa, Masayuki

2002-05-01

126

Shedding of Tumor Necrosis Factor Receptor 1 Induced by Protein A Decreases Tumor Necrosis Factor Alpha Availability and Inflammation during Systemic Staphylococcus aureus Infection.  

PubMed

Staphylococcus aureus infections are an important public health concern due to their increasing incidence and high rates of mortality. The success of S. aureus as a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-?) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients. S. aureus protein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-? receptor 1 (TNFR1). In this study, we demonstrate that S. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-? in vitro and in vivo. The results obtained using a protein A-deficient mutant and tnfr1(-/-) mice strongly suggest that the increased levels of soluble TNFR1 present during experimental S. aureus infection may neutralize circulating TNF-? and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by which S. aureus subverts the host immune response. PMID:24002060

Giai, Constanza; Gonzalez, Cintia; Ledo, Camila; Garofalo, Ailin; Di Genaro, María Silvia; Sordelli, Daniel O; Gomez, Marisa I

2013-09-03

127

Potentiation by tumour necrosis factor-alpha of calcium signals induced by bradykinin and carbachol in human tracheal smooth muscle cells.  

PubMed

The effect of tumour necrosis factor-alpha (TNF alpha) on the increase in cytosolic free calcium ([Ca2+])i induced by carbachol and bradykinin (BK) was investigated in human tracheal smooth muscle cells in culture (TSMC). BK (10(-12)-10(-9) M) and carbachol (10(-7)-10(-3) M) produced a concentration-dependent increase in [Ca2+]i (pD2 = 10.73 +/- 0.05 and 5.57 +/- 0.03 respectively). The increase in [Ca2+]i was significantly enhanced for both agonists in TNF alpha-treated cells (10 ng ml-1 for 24 h). However, pD2 values were not modified (10.78 +/- 0.03 and 5.62 +/- 0.04 for BK and carbachol, respectively) suggesting that no change in the apparent receptor affinity occurred. Thus, TNF alpha induced-alterations in Ca2+ homeostasis in human TSMC may be a key mechanism underlying airway hyperreactivity. PMID:7712026

Amrani, Y; Martinet, N; Bronner, C

1995-01-01

128

Mechanistic links between oxidative/nitrosative stress and tumor necrosis factor alpha in letrozole-induced murine polycystic ovary: biochemical and pathological evidences for beneficial effect of pioglitazone.  

PubMed

This study aimed to investigate the possible relationship between ovarian functionality and the oxidative response during cystogenesis induced by hyperandrogenization with letrozole and examine protective effect of the peroxisome proliferator-activated receptor gamma (PPAR-?) agonist, pioglitazone (PIO), in polycystic ovary (PCO). Ovarian cysts were induced by oral administration of letrozol (1 mg/kg/day) for 21 consecutive days in the female rats. Effective dose of PIO (20 mg/kg/day) was administrated orally for 21 days. Serum estradiol (E), progesterone (P), testosterone (T), and the ovarian immunomodulator prostaglandin E (PGE) were analyzed as biomarkers of ovarian function. To determine the role of oxidative stress in PCO, the level of cellular lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and peroxynitrite (ONOO), and tumor necrosis factor alpha (TNF-?) as a marker of inflammation and apoptosis were measured in serum and the ovaries. Letrozole-induced PCO in rats exhibited a significant increase in LPO and ONOO in serum and ovary while significantly decreased serum and ovarian SOD, CAT, and GPx. Serum T and TNF-?, and ovarian PGE were increased in animals with cysts compared with healthy controls, while E and P diminished. When compared to control group, letrozole-treated group showed irregular sexual cycles, polycystic ovaries characterized by high incidence of sub-capsular ovarian cyst with diminished or scant granulosa cell layer, increased number of atretic pre-antral and antral follicles and absence of corpus luteum. There were almost no primary, secondary, and tertiary follicles observed in PCO rats. All measured parameters were improved by PIO and reached close to normal levels. The present study further supports the role of oxidative/nitrosative stress and infiammatory responses in the pathogenesis of letrozole-induced hyperandrogenic PCO rats. Results indicate that PIO is able to exert direct antioxidative and anti-inflammatory effects on the endocrine, biochemical, and pathological alterations independent of its possible effects mediated via increased insulin sensitivity in hyperandrogenized PCO. PMID:22076494

Rezvanfar, M A; Rezvanfar, M A; Ahmadi, A; Saadi, H A Shojaei; Baeeri, M; Abdollahi, M

2011-11-10

129

Mannose-capped Lipoarabinomannan from Mycobacterium tuberculosis induces soluble tumor necrosis factor receptor production through tumor necrosis factor alpha-converting enzyme activation.  

PubMed

Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-?) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-?-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease. PMID:22927046

Richmond, Jillian M; Duffy, Elizabeth R; Lee, Jinhee; Kaboli, Kavon; Kim, Yun Seong; Remick, Daniel G; Kornfeld, Hardy; Cruikshank, William W

2012-08-27

130

Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces Soluble Tumor Necrosis Factor Receptor Production through Tumor Necrosis Factor Alpha-Converting Enzyme Activation  

PubMed Central

Primary Mycobacterium tuberculosis infection results in granuloma formation in lung tissue. A granuloma encapsulates mycobacterium-containing cells, thereby preventing dissemination and further infection. Tumor necrosis factor alpha (TNF-?) is a host-protective cytokine during M. tuberculosis infection due to its role in promoting and sustaining granuloma formation. TNF activity is regulated through the production of soluble TNF receptors (sTNFRI and sTNFRII). Therefore, we examined the potential production of endogenous sTNFRs during M. tuberculosis infection. Using the murine model of aerosol M. tuberculosis infection, we determined that levels of sTNFR production were elevated in bronchoalveolar lavage fluid 1 month following infection. An investigation of M. tuberculosis cell wall components identified that the known virulence factor mannose-capped lipoarabinomannan (ManLAM) was sufficient to induce sTNFR production, with sTNFRII being produced preferentially compared with sTNFRI. ManLAM stimulated the release of sTNFRs without TNF production, which corresponded to an increase in TNF-?-converting enzyme (TACE) activity. To determine the relevance of these findings, serum samples from M. tuberculosis-infected patients were tested and found to have an increase in the sTNFRII/sTNFRI ratio. These data identify a mechanism by which M. tuberculosis infection can promote the neutralization of TNF and furthermore suggest the potential use of the sTNFRII/sTNFRI ratio as an indicator of tuberculosis disease.

Richmond, Jillian M.; Duffy, Elizabeth R.; Lee, Jinhee; Kaboli, Kavon; Remick, Daniel G.; Kornfeld, Hardy

2012-01-01

131

The receptor for interleukin 3 is selectively induced in human endothelial cells by tumor necrosis factor alpha and potentiates interleukin 8 secretion and neutrophil transmigration.  

PubMed Central

Interleukin (IL)-3 stimulates hemopoiesis in vitro. However, IL-3 is not normally found in bone marrow, raising doubts as to the in vivo role of IL-3. We have found that human umbilical vein endothelial cells (HUVEC) express functional high-affinity receptors for IL-3 after stimulation with tumor necrosis factor alpha (TNF-alpha), IL-1 beta, or lipopolysaccharide, and that this receptor is involved in inflammatory phenomena. TNF-alpha caused time- and dose-dependent up-regulation of mRNA for the IL-3 receptor alpha and beta chains, with maximal effects occurring 16-36 h after stimulation with TNF-alpha at 100 units/ml. Induction of mRNA correlated with protein expression on the cell surface as judged by monoclonal antibody staining and by the ability of HUVEC to specifically bind 125I-labeled IL-3. Scatchard analysis under optimal conditions of TNF-alpha stimulation revealed approximately 1500 IL-3 receptors per cell, which were of a high-affinity class (Kd = 500 pM) only. In contrast to a previous report, receptors for granulocyte-macrophage colony-stimulating factor could not be detected. IL-3 binding to TNF-alpha-activated HUVEC enhanced IL-8 production, E-selection expression, and neutrophil transmigration. The selective induction of a functional IL-3 receptor on endothelial cells suggests that, beyond hemopoiesis, IL-3 may have an important role in chronic inflammation and in allergic diseases. Images Fig. 1 Fig. 2 Fig. 3

Korpelainen, E I; Gamble, J R; Smith, W B; Goodall, G J; Qiyu, S; Woodcock, J M; Dottore, M; Vadas, M A; Lopez, A F

1993-01-01

132

Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin  

Microsoft Academic Search

Background\\/AimsTo investigate the distribution and activation state of circulating monocytes and T-cell subsets, their contribution to tumour necrosis factor-alpha (TNF?) production, and their potential relationship with bacterial products of enteric origin in alcoholic cirrhosis.

Agust??n Albillos; Antonio de la Hera; Eduardo Reyes; Jorge Monserrat; Leticia Muñoz; Mónica Nieto; Alfredo Prieto; Eva Sanz; Melchor Alvarez-Mon

2004-01-01

133

The oestrogen-like effect of 4-hydroxytamoxifen on induction of transforming growth factor alpha mRNA in MDA-MB-231 breast cancer cells stably expressing the oestrogen receptor  

Microsoft Academic Search

Oestrogens and antioestrogens modulate the synthesis of transforming growth factor alpha (TGF-alpha) in breast cancer cells. The purpose of the present report was to examine regulation of TGF-alpha gene expression by oestradiol (E2) and antioestrogens in MDA-MB-231 breast cancer cells transfected with either the wild-type or mutant oestrogen receptor (ER). We recently reported the concentration-dependent E2 stimulation of TGF-alpha mRNA

AS Levenson; DA Tonetti; VC Jordan

1998-01-01

134

Toll-Like Receptor 4Dependent Early Elicited Tumor Necrosis Factor Alpha Expression Is Critical for Innate Host Defense against Bordetella bronchiseptica  

Microsoft Academic Search

Toll-like receptor 4 (TLR4) mediates the response to lipopolysaccharide, and its activation induces the expression of a large number of inflammatory genes, many of which are also induced by other pathogen- associated molecular patterns. Interestingly, the subset of genes that are dependent on TLR4 for optimal expression during gram-negative bacterial infection has not been determined. We have previously shown that

Paul B. Mann; Kelly D. Elder; Mary J. Kennett; Eric T. Harvill

2004-01-01

135

EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa.  

PubMed

Prostaglandin E(2) (PGE(2)) is an inflammatory mediator implicated in several gastrointestinal pathologies that cause diarrhoea. The aim of this study was to establish the contributions of the four different EP receptors (EP(1-4)) to PGE(2)-induced anion secretion in human and mouse colon mucosa. Electrogenic anion secretion (short-circuit current; I(sc)) was measured across colonic mucosae or T84 monolayers placed in Ussing chambers in response to EP receptor agonists and antagonists. PGE(2) and PGE(1)-alcohol increased I(sc) in human colon mucosa, T84 epithelia and mouse colon mucosa, and these responses were inhibited by the EP(4) receptor antagonist, GW627368X alone. In addition, the EP(2) agonist, butaprost increased I(sc) in all three preparations and these responses were inhibited by the non-selective EP(1,2,3) receptor antagonist, AH6809 but not by GW627368X. Conversely, responses mediated by EP(1) and EP(3) receptors were not observed in human colon or T84 monolayers. However, in mouse colon mucosa the EP(3)-preferring agonist, sulprostone reduced I(sc), indicative of G(i?)-signalling. Taken together these results indicate that PGE(2)-induced ion secretion is mediated predominantly by G(s)-coupled EP(4) receptors and also by EP(2) receptors in human mucosa. Furthermore, tumour necrosis factor alpha (TNF?) and interleukin 1beta (IL1?) increased I(sc) and these responses were also inhibited by the EP(4) receptor antagonist in human colon mucosa. This study establishes the EP receptor pharmacology present in human epithelial preparations, and suggests that EP(4) receptors may be a therapeutic target for the treatment of secretory diarrhoea where PGE(2) is implicated in the aetiology. PMID:22732652

Fairbrother, Sian E; Smith, Julia E; Borman, Richard A; Cox, Helen M

2012-06-23

136

Diagnostic Implications of Antigen-Induced Gamma Interferon, Nitric Oxide, and Tumor Necrosis Factor Alpha Production by Peripheral Blood Mononuclear Cells from Mycobacterium bovis-Infected Cattle  

PubMed Central

Bovine tuberculosis in the United States has proven costly to cattle producers as well as to government regulatory agencies. While in vivo responsiveness to mycobacterial antigens is the current standard for the diagnosis of tuberculosis, in vitro assays are gaining acceptance, especially as ancillary or complementary tests. To evaluate in vitro indices of cellular sensitization, antigen-induced gamma interferon (IFN-?), nitric oxide (NO), and tumor necrosis factor alpha (TNF-?) responses by blood mononuclear cells from Mycobacterium bovis-infected cattle were quantified and compared. Using an aerosol model of infection, two doses of each of two strains of M. bovis (95-1315 and HC-2045T) were used to induce a range of IFN-?, NO, and TNF-? responses. Infection-specific increases in NO, but not in IFN-? or TNF-?, were detected in nonstimulated cultures at 48 h, a finding that is indicative of nonspecific activation and spontaneous release of NO. The infective dose of M. bovis organisms also influenced responses. At 34 days postinfection, IFN-?, NO, and TNF-? responses in antigen-stimulated cells from cattle receiving 105 CFU of M. bovis organisms were greater than responses of cells from cattle infected with 103 CFU of M. bovis organisms. The NO response, but not the IFN-? and TNF-? responses, was influenced by infective strains of M. bovis. The TNF-?, NO, and IFN-? responses followed similar kinetics, with strong positive associations among the three readouts. Overall, these findings indicate that NO and TNF-?, like IFN-?, may prove useful as indices for the diagnosis of bovine tuberculosis.

Waters, W. R.; Palmer, M. V.; Whipple, D. L.; Carlson, M. P.; Nonnecke, B. J.

2003-01-01

137

Rapid pathogenesis induced by a vesicular stomatitis virus matrix protein mutant: viral pathogenesis is linked to induction of tumor necrosis factor alpha.  

PubMed

Vesicular stomatitis virus (VSV) matrix (M) protein blocks host mRNA export from the nucleus and thereby inhibits interferon induction in infected cells. M mutants with mutations of methionine 51 (M51) lack this shutoff function. We examined pathogenesis of a VSV M mutant with a deletion of M51 (VSVDeltaM51) after intranasal infection of BALB/c mice and found an unexpected phenotype. Mice that received VSVDeltaM51 experienced a more rapid but overall less severe weight loss than mice that received the recombinant wild-type VSV (rwtVSV). Rapid weight loss was not explained by faster initial replication because VSVDeltaM51 replication was controlled faster than rwtVSV replication in the lungs and did not spread systemically like rwtVSV. This faster control of VSVDeltaM51 correlated with a more rapid induction of interferon in the lung. Because tumor necrosis factor alpha (TNF-alpha) is associated with weight loss, we examined TNF-alpha induction in mice infected with rwtVSV or VSVDeltaM51. We found more-rapid induction of TNF-alpha by the mutant at early times after infection, while rwtVSV induced more TNF-alpha later in infection. This result suggested that TNF-alpha induction might explain both the rapid weight loss caused by the mutant and the overall greater weight loss caused by the rwtVSV. Using TNF-alpha knockout mice (C57BL/6 background), we showed that weight loss following rwtVSV infection was greatly reduced in the absence of TNF-alpha. Although the rapid weight loss caused by VSVDeltaM51 was less pronounced in C57BL/6 mice, it was eliminated in the absence of TNF-alpha. These results indicate a role for TNF-alpha in the pathogenesis of VSV. PMID:16809308

Publicover, Jean; Ramsburg, Elizabeth; Robek, Michael; Rose, John K

2006-07-01

138

Differential regulation in human amnion epithelial and fibroblast cells of prostaglandin E(2) production and prostaglandin H synthase-2 mRNA expression by dexamethasone but not tumour necrosis factor-alpha.  

PubMed

Previous studies have identified both pro-inflammatory cytokines and glucocorticoids as positive regulators of amnion prostaglandin (PG) biosynthesis. The stimulatory effects of dexamethasone (Dex), a glucocorticoid agonist, on prostaglandin endoperoxide H synthase (PGHS)-2 mRNA expression and PG biosynthesis in amnion have been attributed to an atypical response by the mesenchymal cells of the amnion. The objective of this study was to confirm previous findings concerning cell type-dependant Dex-induced upregulation of PGHS-2 mRNA expression and PG production using separated amnion cell populations, in comparison with the effects of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha). Amnion cells from placentae delivered at term by caesarian section were isolated by tryptic digestion and epithelial cells were then separated from mesenchymal cells by differential absorption onto plastic. After 24-72 h, the two cell populations were passaged and sub-cultured. Cells were treated with Dex (10(-9)-10(-6) m) or TNF-alpha (0.1-50 ng/ml) or media alone. Thereafter, PGE(2)production was determined and PGHS-2 mRNA content analysed by a competitive quantitative RT-PCR method established and validated for this study. PGE(2)production in fibroblast-enriched cultures was increased to 310+/-41 per cent (mean+/-sem, n=4 wells per treatment point) of control in the presence of 10(-8) m Dex. Conversely, PGE(2)production in Dex-treated amnion epithelial cells was decreased to 67+/-24 per cent of control. Altered PGE(2)biosynthesis was accompanied by the upregulation of PGHS-2 mRNA in amnion fibroblasts but not in epithelial cells. TNF-alpha increased PG output and PGHS-2 expression independent of cell type. Glucocorticoids therefore appear to have opposing effects on PG biosynthesis in the two major cellular components of the human amnion. PMID:10736244

Blumenstein, M; Hansen, W R; Deval, D; Mitchell, M D

139

Protein kinase C-{beta}, fibronectin, {alpha}{sub 5}{beta}{sub 1}-integrin and tumor necrosis factor-{alpha} are required for phorbol diester-induced apoptosis in human myeloid leukemia cells in human myeloid leukemia cells.  

SciTech Connect

The human myeloid HL-60 cell line and its cell variant HL-525 were used to study signaling events leading to apoptosis induction by phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC) enzymes. Unlike parental cells, HL-525 cells are PKC-{beta} deficient and resistant to PMA-induced apoptosis. These cells regain susceptibility to apoptosis induction after transfection with a PKC-{beta} expression vector. By using this vector and specific neutralizing monoclonal antibodies (mAbs), it was established that PMA-induced apoptosis also called for an interaction between cell-surface {alpha}{sub 5}{beta}{sub 1}-integrin and its deposited ligand fibronectin (FN), which is downstream of PKC-{beta} activation. Experiments with mAbs, the PKC-{beta} vector, and exogenous FN revealed that the next step entailed an interaction between secreted tumor necrosis factor-{alpha} and its type I receptor. By using a sphingomyelinase inhibitor, it was concluded that the subsequent step involved ceramide production. Moreover, a permeable ceramide was effective in inducing apoptosis in both HL-60 and HL-525 cells, and this induction was caspase-1 and/or -4 dependent because an inhibitor of these caspases abrogated the induced apoptosis. Based on these and related differentiation studies, we conclude that the above signaling events, the early ones in particular, are shared with PMA-induced macrophage differentiation in the HL-60 cells. It is likely that once these cells acquire their macrophage phenotype and perform their tasks, they become superfluous and are eliminated from the body by a self-triggered apoptotic process that involves our proposed signaling scheme.

Laouar, A.; Glesne, D.; Huberman, E.

2001-12-01

140

Ketamine inhibits tumor necrosis factor-{alpha} and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation  

SciTech Connect

Our previous study showed that ketamine, an intravenous anesthetic agent, has anti-inflammatory effects. In this study, we further evaluated the effects of ketamine on the regulation of tumor necrosis factor-{alpha} (TNF-{alpha}) and interlukin-6 (IL-6) gene expressions and its possible signal-transducing mechanisms in lipopolysaccharide (LPS)-activated macrophages. Exposure of macrophages to 1, 10, and 100 {mu}M ketamine, 100 ng/ml LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. A concentration of 1000 {mu}M of ketamine alone or in combined treatment with LPS caused significant cell death. Administration of LPS increased cellular TNF-{alpha} and IL-6 protein levels in concentration- and time-dependent manners. Meanwhile, treatment with ketamine concentration- and time-dependently alleviated the enhanced effects. LPS induced TNF-{alpha} and IL-6 mRNA syntheses. Administration of ketamine at a therapeutic concentration (100 {mu}M) significantly inhibited LPS-induced TNF-{alpha} and IL-6 mRNA expressions. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA into macrophages decreased cellular TLR4 levels. Co-treatment of macrophages with ketamine and TLR4 siRNA decreased the LPS-induced TNF-{alpha} and IL-6 productions more than alone administration of TLR4 siRNA. LPS stimulated phosphorylation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos from the cytoplasm to nuclei. However, administration of ketamine significantly decreased LPS-induced activation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos. LPS increased the binding of nuclear extracts to activator protein-1 consensus DNA oligonucleotides. Administration of ketamine significantly ameliorated LPS-induced DNA binding activity of activator protein-1. Therefore, a clinically relevant concentration of ketamine can inhibit TNF-{alpha} and IL-6 gene expressions in LPS-activated macrophages. The suppressive mechanisms occur through suppression of TLR4-mediated sequential activations of c-Jun N-terminal kinase and activator protein-1.

Wu, G.-J. [Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan (China); Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Chen, T.-L. [Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Department of Anesthesiology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan (China); Ueng, Y.-F. [National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Chen, R.-M. [Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)], E-mail: rmchen@tmu.edu.tw

2008-04-01

141

Hantaan Virus Nucleocapsid Protein Binds to Importin   Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B  

Microsoft Academic Search

Hantaviruses such as Hantaan virus (HTNV) and Andes virus cause two human diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome, respectively. For both, disease pathogenesis is thought to be immunologically mediated and there have been numerous reports of patients with elevated levels of proinflamma- tory and inflammatory cytokines, including tumor necrosis factor alpha (TNF-), in their sera. Multiple

Shannon L. Taylor; Natalia Frias-Staheli; A. Garcia-Sastre; Connie S. Schmaljohn

2009-01-01

142

Effects of selective tumor necrosis factor-alpha inhibition to pain-behavioral changes caused by nucleus pulposus-induced damage to the spinal nerve in rats  

Microsoft Academic Search

Application of nucleus pulposus to the spinal nerve and displacement of the adjacent nerve results in behavioral changes in rats. It has been reported that treatment with the tumor necrosis factor-alpha (TNF?) inhibitor, infliximab, significantly reduces spontaneous pain behavior in this animal model. However, there have been no reports of the effects of infliximab on mechanical or thermal hyperalgesia using

Yasuaki Murata; Kjell Olmarker; Ichiro Takahashi; Kazuhisa Takahashi; Björn Rydevik

2005-01-01

143

Adalimumab (tumor necrosis factor-blocker) reduces the expression of glial fibrillary acidic protein immunoreactivity increased by exogenous tumor necrosis factor alpha in an organotypic culture of porcine neuroretina  

PubMed Central

Purpose To determine if exogenous addition of tumor necrosis factor alpha (TNF?) exacerbates retinal reactive gliosis in an organotypic culture of porcine neuroretina and to evaluate if concomitant adalimumab, a TNF-blocker, diminishes it. Methods Porcine retinal explants from 20 eyeballs were cultured. Cultures with 100 pg/ml TNF?, 10 µg/ml adalimumab, 100 pg/ml TNF? plus 10 µg/ml adalimumab, or controls without additives were maintained for 9 days. Freshly detached retinas were processed in parallel. TNF? levels in control culture supernatants were quantified with enzyme-linked immunosorbent assay. Cryostat sections were doubly immunostained for glial fibrillary acidic protein (GFAP), a marker for reactive gliosis, and cellular retinaldehyde-binding protein (CRALBP), a marker for Müller cells. Sections were also labeled with the isolectin IB4, a label for microglia/macrophages. Results TNF? in control culture supernatants was detected only at day 1. Compared to the fresh neuroretinal samples, upregulation of GFAP and downregulation of CRALBP occurred during the 9 days of culture. Exogenous TNF? stimulated glial cells to upregulate GFAP and downregulate CRALBP immunoreactivity. TNF?-treated cultures also initiated the growth of gliotic membranes and underwent retinal disorganization. Adalimumab inhibited the spontaneous increases in GFAP and maintained CRALBP. In combination with TNF?, adalimumab reduced GFAP expression and conserved CRALBP, with only slight retinal disorganization. No appreciable changes in IB4 labeling were observed under the different culture conditions. Conclusions In cultured porcine neuroretina, spontaneous reactive gliosis and retinal disorganization were exacerbated by exogenous TNF?. Adalimumab reduced spontaneous changes and those induced by TNF?. Therefore, inhibiting TNF? may represent a novel approach to controlling retinal fibrosis observed in some human diseases.

Garcia-Gutierrez, M.T.; Srivastava, G.K.; Gayoso, M.J.; Gonzalo-Orden, J.M.; Pastor, J.C.

2013-01-01

144

Promotion of mouse fibroblast collagen gene expression by mast cells stimulated via the Fc epsilon RI. Role for mast cell-derived transforming growth factor beta and tumor necrosis factor alpha  

PubMed Central

Chronic allergic diseases and other disorders associated with mast cell activation can also be associated with tissue fibrosis, but a direct link between mast cell mediator release and fibroblast collagen gene expression has not been established. Using in situ hybridization, we show that the elicitation of an IgE-dependent passive cutaneous anaphylaxis (PCA) reaction in mice results in a transient, but marked augmentation of steady state levels of type alpha-1 (I) collagen mRNA in the dermis. While peak levels of collagen mRNA expression in the skin are observed 16-24 h after mast cell activation, substantial numbers of dermal cells are strongly positive for collagen mRNA at 1 and 2 h after antigen challenge, before circulating inflammatory cells are recruited into the tissues. Furthermore, experiments in mast cell- reconstituted or genetically mast cell-deficient WBB6F1-W/Wv mice demonstrate that the increased expression of collagen mRNA at sites of PCA reactions is entirely mast cell dependent. In vitro studies show that the supernatants of mouse serosal mast cells activated via the Fc epsilon RI markedly increase type alpha-1 (I) collagen mRNA levels in mouse embryonic skin fibroblasts, and also upregulate collagen secretion by these cells. The ability of mast cell supernatants to induce increased steady state levels of collagen mRNA in mouse skin fibroblasts is markedly diminished by absorption with antibodies specific for either of two mast cell-derived cytokines, transforming growth factor beta (TGF-beta 1) or tumor necrosis factor alpha (TNF- alpha), and is eliminated entirely by absorption with antibodies against both cytokines. Taken together, these findings demonstrate that IgE-dependent mouse mast cell activation can induce a transient and marked increase in steady state levels of type alpha-1 (I) collagen mRNA in dermal fibroblasts and that mast cell-derived TGF-beta 1 and TNF-alpha importantly contribute to this effect.

1994-01-01

145

Intraneural injection of interleukin-1? and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain  

Microsoft Academic Search

Proinflammatory cytokines are mediators of inflammatory and neuropathic pain. Here, we investigated pain-related behavior in rats after intraneural injection of different doses of rat recombinant interleukin-1? (rrIL-1?) and tumor necrosis factor-alpha (rrTNF) into the sciatic nerve. Doses ranged between 0.25 and 2500pg\\/ml for rrIL-1? and 0.25–250pg\\/ml for rrTNF. Thermal hyperalgesia as measured according to the Hargreaves method was most prominent

Marek Zelenka; Maria Schäfers; Claudia Sommer

2005-01-01

146

A Role for Protein Phosphatase 2A in Regulating p38 Mitogen Activated Protein Kinase Activation and Tumor Necrosis Factor-Alpha Expression during Influenza Virus Infection  

PubMed Central

Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF)-alpha through p38 mitogen activated protein kinase (MAPK). However, the detailed mechanisms of p38MAPK activation and TNF-alpha hyperinduction following influenza virus infections are not known. Negative feedback regulations of cytokine expression play important roles in avoiding overwhelming production of proinflammatory cytokines. Here we hypothesize that protein phosphatases are involved in the regulation of cytokine expressions during influenza virus infection. We investigated the roles of protein phosphatases including MAPK phosphatase-1 (MKP-1) and protein phosphatase type 2A (PP2A) in modulating p38MAPK activation and downstream TNF-alpha expressions in primary human monocyte-derived macrophages (PBMac) infected with H9N2/G1 or H1N1 influenza virus. We demonstrate that H9N2/G1 virus activated p38MAPK and hyperinduced TNF-alpha production in PBMac when compared with H1N1 virus. H9N2/G1 induced PP2A activity in PBMac and, with the treatment of a PP2A inhibitor, p38MAPK phosphorylation and TNF-alpha production were further increased in the virus-infected macrophages. However, H9N2/G1 did not induce the expression of PP2A indicating that the activation of PP2A is not mediated by p38MAPK in virus-infected PBMac. On the other hand, PP2A may not be the targets of H9N2/G1 in the upstream of p38MAPK signaling pathways since H1N1 also induced PP2A activation in primary macrophages. Our results may provide new insights into the control of cytokine dysregulation.

Law, Anna H. Y.; Tam, Alex H. M.; Lee, Davy C. W.; Lau, Allan S. Y.

2013-01-01

147

A Role for Protein Phosphatase 2A in Regulating p38 Mitogen Activated Protein Kinase Activation and Tumor Necrosis Factor-Alpha Expression during Influenza Virus Infection.  

PubMed

Influenza viruses of avian origin continue to pose pandemic threats to human health. Some of the H5N1 and H9N2 virus subtypes induce markedly elevated cytokine levels when compared with the seasonal H1N1 virus. We previously showed that H5N1/97 hyperinduces tumor necrosis factor (TNF)-alpha through p38 mitogen activated protein kinase (MAPK). However, the detailed mechanisms of p38MAPK activation and TNF-alpha hyperinduction following influenza virus infections are not known. Negative feedback regulations of cytokine expression play important roles in avoiding overwhelming production of proinflammatory cytokines. Here we hypothesize that protein phosphatases are involved in the regulation of cytokine expressions during influenza virus infection. We investigated the roles of protein phosphatases including MAPK phosphatase-1 (MKP-1) and protein phosphatase type 2A (PP2A) in modulating p38MAPK activation and downstream TNF-alpha expressions in primary human monocyte-derived macrophages (PBMac) infected with H9N2/G1 or H1N1 influenza virus. We demonstrate that H9N2/G1 virus activated p38MAPK and hyperinduced TNF-alpha production in PBMac when compared with H1N1 virus. H9N2/G1 induced PP2A activity in PBMac and, with the treatment of a PP2A inhibitor, p38MAPK phosphorylation and TNF-alpha production were further increased in the virus-infected macrophages. However, H9N2/G1 did not induce the expression of PP2A indicating that the activation of PP2A is not mediated by p38MAPK in virus-infected PBMac. On the other hand, PP2A may not be the targets of H9N2/G1 in the upstream of p38MAPK signaling pathways since H1N1 also induced PP2A activation in primary macrophages. Our results may provide new insights into the control of cytokine dysregulation. PMID:23549267

Law, Anna H Y; Tam, Alex H M; Lee, Davy C W; Lau, Allan S Y

2013-04-02

148

Requirement of tumor necrosis factor alpha and nuclear factor-kappaB in the induction by IFN-gamma of inducible nitric oxide synthase in macrophages.  

PubMed

IFN-gamma induces NO production, inducible NO synthase (iNOS) protein, and promoter expression in mouse macrophage cells. Mutation of IFN regulatory factor 1 responsive element, gamma-activated site, as well as NF-kappaB elements in the murine iNOS promoter strongly reduced IFN-gamma-induced iNOS transcriptional activity. The role of NF-kappaB activation in iNOS induction by IFN-gamma was corroborated by overexpression of the NF-kappaB inhibitory protein IkappaBalpha, which inhibited iNOS promoter activity induced by IFN-gamma. In addition, IFN-gamma treatment induced p65 binding to the iNOS promoter by chromatin immunoprecipitation assay and NF-kappaB binding to DNA by EMSA, although with a delayed kinetics, suggesting an indirect autocrine role for another cytokine produced in response to IFN-gamma. It is interesting that we found that IFN-gamma induced TNF-alpha secretion, and the induction of iNOS expression by IFN-gamma was abolished in primary peritoneal macrophages from TNF-alpha-deficient (TNF-alpha-/-) mice or in RAW 264.7 cells treated with anti-TNF-alpha neutralizing antibodies. Moreover, exogenous addition of recombinant mouse TNF-alpha restored iNOS expression induced by IFN-gamma in TNF-alpha-/- mice. It is intriguing that NF-kappaB binding to DNA in response to IFN-gamma treatment was absent in TNF-alpha-/- mice. Taken together, our data suggest that the TNF-alpha produced in response to IFN-gamma is required for iNOS induction by activating NF-kappaB transcription factor. PMID:17035338

Vila-del Sol, Virginia; Díaz-Muñoz, Manuel D; Fresno, Manuel

2006-10-11

149

Tumour necrosis factor-alpha-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx.  

PubMed

The present study was undertaken to determine how tumour necrosis factor-alpha (TNF-alpha) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 beta-cells. TNF-alpha pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, K(ATP) channels, Ca(2)(+) channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-alpha reduced the glucose-stimulated influx of Ca(2)(+). The TNF-alpha treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-kappaB inflammatory signals, since TNF-alpha increased phospho-JNK and phospho-p38 and reduced I kappaB levels. Inhibitors of these signaling pathways prevented the TNF-alpha-induced reduction of the Ca(2)(+) influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-alpha receptor to the JNK/p38 and NK-kappaB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-kappaB, and reduced the glucose-stimulated Ca(2)(+) influx and GSIS. The reduction of the Ca(2)(+) influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-kappaB. These data demonstrate that TNF-alpha inhibits GSIS by reducing the glucose-stimulated Ca(2)(+) influx, possibly through the activation of JNK and p38 MAPK and NF-kappaB inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes. PMID:18593820

Kim, Hyo-Eun; Choi, Sung-E; Lee, Soo-Jin; Lee, Ji-Hyun; Lee, Youn-Jung; Kang, Sang Sun; Chun, Jaesun; Kang, Yup

2008-07-01

150

Modulation of transforming growth factor alpha-dependent expression of epidermal growth factor receptor gene by transforming growth factor beta, triiodothyronine, and retinoic acid.  

PubMed

We have investigated the actions of transforming growth factor (TGF) type alpha on epidermal growth factor (EGF) receptor mRNA expression in MDA-468 human mammary carcinoma cells in serum-free media. We found that exposure of MDA-468 cells to TGF alpha results in elevated levels of EGF receptor mRNA. This increase in mRNA accumulation showed time and dose dependence. Addition of TGF beta 1 enhanced the accumulation of EGF receptor mRNA induced by TGF alpha in a time- and dose-dependent manner. We also found that triiodothyronine at physiological concentrations exerts synergistic control on the action of TGF alpha alone, or in association with TGF beta 1, on EGF receptor mRNA expression. Similarly, retinoic acid treatment also enhanced in a time- and dose-dependent manner the TGF alpha-dependent response of EGF receptor mRNA and acted synergistically with TGF beta 1. The results described here suggest that optimum regulation of EGF receptor gene expression by TGF alpha is a complex process involving synergistic interactions with heterologous growth factors and hormones. PMID:2613750

Fernandez-Pol, J A; Klos, D J; Hamilton, P D

1989-11-01

151

Tumor necrosis factor alpha inducing spatial interactions between calcium-sensing receptor and L-type voltage-dependent calcium channel.  

PubMed

The temporal and spatial regulation of intracellular calcium concentration ([Ca(2+)](i)) is very crucial for maintaining calcium ion homeostasis within cells, and consequently in the regulation of cellular functions such as beta cell replication and differentiation, insulin secretion, and apoptosis. Calcium ion regulatory proteins playing major roles in these processes include L-type voltage-dependent calcium channels (L-type VDCCs) and calcium-sensing receptors (CaRs). Tumor necrosis factor alpha (TNF-alpha), a cytokine, is widely known to activate nuclear factor-kappa B (NF-kappaB) transcription in beta cells. Confocal fluorescence imaging data suggest increased co-localization of CaRs with L-type VDCCs upon treatment of beta cells with TNF-alpha, thereby indicating increased membrane-delimited spatial interactions between these two membrane proteins. PMID:19120320

Parkash, Jai

2008-12-01

152

Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells  

PubMed Central

Although cryptotanshinone (CT) was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1? in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1? accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1? siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1? during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1? to VEGF promoter. Furthermore, CT at 10?mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1?, AEG1, and VEGF as a potent chemotherapeutic agent.

Lee, Hyo-Jeong; Jung, Deok-Beom; Sohn, Eun Jung; Kim, Hanna Hyun; Park, Moon Nyeo; Lew, Jae-Hwan; Lee, Seok Geun; Kim, Bonglee; Kim, Sung-Hoon

2012-01-01

153

Regulation of Lipopolysaccharide-Induced Translation of Tumor Necrosis Factor-Alpha by the Toll-Like Receptor 4 Adaptor Protein TRAM  

PubMed Central

Lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-? requires the recruitment of two pairs of adaptors to the Toll-like receptor 4 cytoplasmic domain. The contribution of one pair – Toll-interleukin-1 receptor domain-containing adaptor inducing interferon-? (TRIF) and TRIF-related adaptor molecule (TRAM) – to TNF-? expression is not well understood. To clarify this issue, we studied TRAM knockout bone marrow-derived macrophages (BMDM). LPS-stimulated TRAM-deficient BMDM had decreased TNF-? protein expression even at times when TNF-? mRNA levels were normal, suggesting impaired translation. Consistent with this idea, knockdown of TRAM in RAW264.7 macrophages decreased translation of a reporter controlled by the TNF-? 3? untranslated region, while transfection of TRAM in HEK293T cells increased translation of this reporter. Also consistent with a role for TRAM in TNF-? translation, LPS-induced activation of MK2, a kinase involved in this process, was impaired in TRAM-deficient BMDM. TRIF did not increase translation of the TNF-? 3? untranslated region reporter when expressed in HEK293T cells. However, BMDM that lacked functional TRIF produced reduced levels of TNF-? protein in response to LPS despite normal amounts of the mRNA. Unlike BMDM, LPS-stimulated TRAM-deficient peritoneal macrophages displayed equivalent reductions in TNF-? protein and mRNA. Our results indicate that TRAM- and TRIF-dependent signals have a previously unappreciated, cell type-specific role in regulating TNF-? translation. Copyright © 2011 S. Karger AG, Basel

Wang, Lijian; Trebicka, Estela; Fu, Ying; Waggoner, Lisa; Akira, Shizuo; Fitzgerald, Katherine A.; Kagan, Jonathan C.; Cherayil, Bobby J.

2011-01-01

154

Eukaryotic translation initiation factor 5A induces apoptosis in colon cancer cells and associates with the nucleus in response to tumour necrosis factor {alpha} signalling  

SciTech Connect

Eukaryotic translation initiation factor 5A (eIF5A) is thought to function as a nucleocytoplasmic shuttle protein. There are reports of its involvement in cell proliferation, and more recently it has also been implicated in the regulation of apoptosis. In the present study, we examined the effects of eIF5A over-expression on apoptosis and of siRNA-mediated suppression of eIF5A on expression of the tumour suppressor protein, p53. Over-expression of either eIF5A or a mutant of eIF5A incapable of being hypusinated was found to induce apoptosis in colon carcinoma cells. Our results also indicate that eIF5A is required for expression of p53 following the induction of apoptosis by treatment with Actinomycin D. Depiction of eIF5A localization by indirect immunofluorescence has indicated, for the first time, that the protein is rapidly translocated from the cytoplasm to the nucleus by death receptor activation or following treatment with Actinomycin D. These findings collectively indicate that unhypusinated eIF5A may have pro-apoptotic functions and that eIF5A is rapidly translocated to the nucleus following the induction of apoptotic cell death.

Taylor, Catherine A. [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Sun Zhong [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Cliche, Dominic O. [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Ming, Hong [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Eshaque, Bithi [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Jin Songmu [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Hopkins, Marianne T. [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Thai, Boun [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada); Thompson, John E. [Department of Biology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario, N2L 3G1 (Canada)]. E-mail: jet@sciborg.uwaterloo.ca

2007-02-01

155

An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-alpha.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce insulin resistance in cultured cells as well as in animal models. The aim of this study was to map the in vivo mechanism whereby TNF-alpha contributes to the pathogenesis of impaired insulin signaling, using obese and lean Zucker rats in which TNF-alpha activity was inhibited through adenovirus-mediated gene transfer. We employed a replication-incompetent adenovirus-5 (Ad5) vector to endogenously express a TNF inhibitor (TNFi) gene, which encodes a chimeric protein consisting of the extracellular domain of the human 55-kDa TNF receptor joined to a mouse IgG heavy chain. Control animals consisted of rats infected with the same titer of adenovirus carrying the lac-z complementary DNA, encoding for beta-galactosidase. There was a significant reduction in plasma insulin and free fatty acid levels in TNFi obese rats 2 days following Ad5 administration. The peripheral insulin sensitivity index was 50% greater, whereas hepatic glucose output was completely suppressed during hyperinsulinemic glucose clamps in TNFi obese animals, with no differences observed between the two lean groups. The improvement in peripheral and hepatic sensitivity to insulin seen in the obese animals was independent of insulin receptor (IR) number and insulin binding affinity for IR. However, TNF-alpha neutralization led to a 2.5-fold increase in tyrosine phosphorylation of IR in skeletal muscle, whereas this was unchanged in liver. There was also a 4-fold increase in particulate protein tyrosine phosphatase activity of skeletal muscle in TNFi obese animals vs. beta-galactosidase controls, whereas protein tyrosine phosphatase activity in liver was unchanged. These results suggest that TNF-alpha is a mediator of insulin resistance in obesity and may modulate IR signaling in skeletal muscle and liver through different pathways. TNF-alpha may affect insulin action in the liver either at sites distal to the IR or indirectly, possibly because of increased provision of gluconeogenic substrates or altered counterregulation. In addition, the Ad5-mediated gene delivery system employed here provides an in vivo model that is efficient and economical for exploring mechanisms involved in TNF-alpha-induced insulin resistance in various genetic models of obesity-linked diabetes. PMID:9832430

Cheung, A T; Ree, D; Kolls, J K; Fuselier, J; Coy, D H; Bryer-Ash, M

1998-12-01

156

Protective effect of photodegradation product of nifedipine against tumor necrosis factor alpha-induced oxidative stress in human glomerular endothelial cells.  

PubMed

Recently, increasing evidence suggests that the antihypertensive drug nifedipine acts as a protective agent for endothelial cells, and that the activity is unrelated to its calcium channel blocking. Nitrosonifedipine (NO-NIF) is metabolically and photochemically produced from nifedipine, and NO-NIF has been recognized as a contaminant of nifedipine because it has no antihypertensive effect. Treatment of tumor necrosis factor-? (TNF-?) suppressed the cell viability and facilitated the expression of Inter-Cellular Adhesion Molecule 1(ICAM-1) in human glomerular endothelial cells (HGECs) though, pretreatment of NO-NIF significantly recovered the TNF-?-induced cell damage to the same extent as Trolox-C did, and suppressed the ICAM-1 expression in a concentration dependent manner. In addition, NO-NIF inhibited the cell toxicity induced by cumene hydroperoxide, which hampers the integrity of cell membrane through oxidative stress, as effective as Trolox-c. These data suggest that NO-NIF is a candidate for a new class of antioxidative drug that protect cells against oxidative stress in glomerular endothelial cells. PMID:21372496

Fukuhara, Yayoi; Tsuchiya, Koichiro; Horinouchi, Yuya; Tajima, Soichiro; Kihira, Yoshitaka; Hamano, Shuichi; Kawazoe, Kazuyoshi; Ikeda, Yasumasa; Ishizawa, Keisuke; Tomita, Shuhei; Tamaki, Toshiaki

2011-02-01

157

Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha  

PubMed Central

Introduction The present study assessed the potential functions of interleukin (IL)-32? on inflammatory arthritis and endotoxin shock models using IL-32? transgenic (Tg) mice. The potential signaling pathway for the IL-32-tumor necrosis factor (TNF)? axis was analyzed in vitro. Methods IL-32? Tg mice were generated under control of a ubiquitous promoter. Two disease models were used to examine in vivo effects of overexpressed IL-32?: Toll-like receptor (TLR) ligand-induced arthritis developed using a single injection of lipopolysaccharide (LPS) or zymosan into the knee joints; and endotoxin shock induced with intraperitoneal injection of LPS and D-galactosamine. TNF? antagonist etanercept was administered simultaneously with LPS in some mice. Using RAW264.7 cells, in vitro effects of exogenous IL-32? on TNF?, IL-6 or macrophage inflammatory protein 2 (MIP-2) production were assessed with or without inhibitors for nuclear factor kappa B (NF?B) or mitogen-activated protein kinase (MAPK). Results Single injection of LPS, but not zymosan, resulted in development of severe synovitis with substantial articular cartilage degradation in knees of the Tg mice. The expression of TNF? mRNA in inflamed synovia was highly upregulated in the LPS-injected Tg mice. Moreover, the Tg mice were more susceptive to endotoxin-induced lethality than the wild-type control mice 48 hours after LPS challenge; but blockade of TNF? by etanercept protected from endotoxin lethality. In cultured bone marrow cells derived from the Tg mice, overexpressed IL-32? accelerated production of TNF? upon stimulation with LPS. Of note, exogenously added IL-32? alone stimulated RAW264.7 cells to express TNF?, IL-6, and MIP-2 mRNAs. Particularly, IL-32? -induced TNF?, but not IL-6 or MIP-2, was inhibited by dehydroxymethylepoxyquinomicin (DHMEQ) and U0126, which are specific inhibitors of nuclear factor kappa B (NF?B) and extracellular signal regulated kinase1/2 (ERK1/2), respectively. Conclusions These results show that IL-32? contributed to the development of inflammatory arthritis and endotoxin lethality. Stimulation of TLR signaling with LPS appeared indispensable for activating the IL-32?-TNF? axis in vivo. However, IL-32? alone induced TNF? production in RAW264.7 cells through phosphorylation of inhibitor kappa B (I?B) and ERK1/2 MAPK. Further studies on the potential involvement of IL-32?-TNF? axis will be beneficial in better understanding the pathology of autoimmune-related arthritis and infectious immunity.

2012-01-01

158

Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate.  

PubMed

Although 3':5' cyclic adenosine monophosphate (cAMP) is known to modulate cytokine production in a number of cell types, little information exists regarding cAMP-mediated effects on this synthetic function of human airway smooth-muscle (HASM) cells. We examined the effect of increasing intracellular cAMP concentration ([cAMP](i)) on tumor necrosis factor (TNF)-alpha-induced regulated on activation, normal T cells expressed and secreted (RANTES) and interleukin (IL)-6 secretion from cultured HASM cells. Pretreatment of HASM with prostaglandin (PG) E(2), forskolin, or dibutyryl cAMP inhibited TNF-alpha-induced RANTES secretion but increased TNF-alpha-induced IL-6 secretion. Moreover, stimulation with PGE(2), forskolin, or dibutyryl cAMP alone increased basal IL-6 secretion in a concentration-dependent manner. SB 207499, a specific phosphodiesterase type 4 inhibitor, augmented the inhibitory effects of PGE(2) and forskolin on TNF-alpha-induced RANTES. Collectively, these data demonstrate that increasing [cAMP](i) in HASM effectively increases IL-6 secretion but reduces RANTES secretion promoted by TNF-alpha. Reverse transcriptase/polymerase chain reaction and ribonuclease protection assays suggested that these opposite effects of increased [cAMP](i) on TNF-alpha- induced IL-6 and RANTES secretion may occur at the transcriptional level. Accordingly, we examined the effects of TNF- alpha and cAMP on the regulation of nuclear factor (NF)-kappaB, a transcription factor known to modulate cytokine synthesis in numerous cell types. Stimulation of HASM cells with TNF-alpha increased NF-kappaB DNA-binding activity. However, increased [cAMP](i) in HASM neither activated NF-kappaB nor altered TNF-alpha- induced NF-kappaB DNA-binding activity. These results were confirmed using a NF-kappaB-luciferase reporter assay. Together, our data suggest that TNF-alpha-induced IL-6 and RANTES secretion may be associated with NF-kappaB activation, and that inhibition of TNF-alpha-stimulated RANTES secretion and augmentation of IL-6 secretion by increased [cAMP](i) in HASM cells occurs via an NF-kappaB-independent mechanism. PMID:11104733

Ammit, A J; Hoffman, R K; Amrani, Y; Lazaar, A L; Hay, D W; Torphy, T J; Penn, R B; Panettieri, R A

2000-12-01

159

N-Acetyl-cysteine inhibition of encephalomyelitis Theiler's virus-induced nitric oxide and tumour necrosis factor-alpha production by murine astrocyte cultures.  

PubMed

The pathological mechanisms that cause central nervous system (CNS) dysfunction in most neurological diseases are not well established. Theiler's murine encephalomyelitis virus (TMEV) is known to interact with cells of the CNS and its intracerebral inoculation to susceptible mice strains causes neurological disorders resembling multiple sclerosis (MS). In this study, we reported that primary astrocyte cultures from SJL/J susceptible mice when infected with TMEV released important amounts of nitrites (NO2-) to the culture medium, as measured in the supernatants 24 hours after infection. In addition, we observed an increment in the production of tumour necrosis factor alpha (TNF-alpha) by susceptible SJL/J strain derived astrocytes infected with TMEV. The treatment with the thiolic antioxidant N-acetyl-cysteine partially suppressed the virus-stimulated production of nitric oxide and TNF-alpha, in a dose response fashion. These results indicate that during viral infection astrocytes are an important cellular source of nitric oxide and TNF-alpha, substances which play important roles during CNS inflammatory events. The effects of the antioxidant N-acetyl-cysteine, modulating the production of the above compounds by TMEV-infected astrocytes may be a significant factor in preventing CNS demyelination. PMID:10609881

Molina-Holgado, F; Hernanz, A; De la Fuente, M; Guaza, C

1999-01-01

160

Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages.  

PubMed Central

Cell invasion by Trypanosoma cruzi and its intracellular replication are essential for continuation of the parasite life cycle and for production of Chagas' disease. T. cruzi is able to replicate in nucleated cells and can be killed by activated macrophages. Gamma interferon (IFN-gamma) is one of the major stimuli for the activation of macrophages and has been shown to be a key activation factor for the killing of intracellular parasites through a mechanism dependent upon nitric oxide (NO) biosynthesis. We show that although the addition of exogenous tumor necrosis factor alpha (TNF-alpha) does not potentiate the trypanocidal activity of IFN-gamma in vitro, treatment of resistant C57BI/6 mice with an anti-TNF-alpha monoclonal antibody increased parasitemia and mortality. In addition, the anti-TNF-alpha-treated animals had decreased NO production, both in vivo and in vitro, suggesting an important role for TNF-alpha in controlling infection. In order to better understand the role of TNF-alpha in the macrophage-mediating killing of parasites, cultures of T. cruzi-infected macrophages were treated with an anti-TNF-alpha monoclonal antibody. IFN-gamma-activated macrophages failed to kill intracellular parasites following treatment with 100 micrograms of anti-TNF-alpha. In these cultures, the number of parasites released at various time points after infection was significantly increased while NO production was significantly reduced. We conclude that IFN-gamma-activated macrophages produce TNF-alpha after infection by T. cruzi and suggest that this cytokine plays a role in amplifying NO production and parasite killing.

Silva, J S; Vespa, G N; Cardoso, M A; Aliberti, J C; Cunha, F Q

1995-01-01

161

Extrachromosomal inducible expression.  

PubMed

Inducible expression systems are very convenient for proteins that induce strong side effects such as retardation of growth or development and are essential for the expression of toxic proteins. In this chapter we describe the doxycycline-inducible expression system, optimized for the controlled expression in. Two types of inducible plasmids are presented, in which transcription is induced by either adding or removing doxycycline, respectively. Detailed protocols are provided for the construction of the plasmids and the inducible expression of the target protein. PMID:23494312

Veltman, Douwe M; Van Haastert, Peter J M

2013-01-01

162

Constitutive stabilization of hypoxia-inducible factor alpha selectively promotes the self-renewal of mesenchymal progenitors and maintains mesenchymal stromal cells in an undifferentiated state.  

PubMed

With the increasing use of culture-expanded mesenchymal stromal cells (MSCs) for cell therapies, factors that regulate the cellular characteristics of MSCs have been of major interest. Oxygen concentration has been shown to influence the functions of MSCs, as well as other normal and malignant stem cells. However, the underlying mechanisms of hypoxic responses and the precise role of hypoxia-inducible factor-1? (Hif-1?), the master regulatory protein of hypoxia, in MSCs remain unclear, due to the limited span of Hif-1? stabilization and the complex network of hypoxic responses. In this study, to further define the significance of Hif-1? in MSC function during their self-renewal and terminal differentiation, we established adult bone marrow (BM)-derived MSCs that are able to sustain high level expression of ubiquitin-resistant Hif-1? during such long-term biological processes. Using this model, we show that the stabilization of Hif-1? proteins exerts a selective influence on colony-forming mesenchymal progenitors promoting their self-renewal and proliferation, without affecting the proliferation of the MSC mass population. Moreover, Hif-1? stabilization in MSCs led to the induction of pluripotent genes (oct-4 and klf-4) and the inhibition of their terminal differentiation into osteogenic and adipogenic lineages. These results provide insights into the previously unrecognized roles of Hif-1? proteins in maintaining the primitive state of primary MSCs and on the cellular heterogeneities in hypoxic responses among MSC populations. PMID:24071737

Park, In-Ho; Kim, Kwang-Ho; Choi, Hyun-Kyung; Shim, Jae-Seung; Whang, Soo-Young; June Hahn, Sang; Kwon, Oh-Joo; Oh, Il-Hoan

2013-09-27

163

Constitutive stabilization of hypoxia-inducible factor alpha selectively promotes the self-renewal of mesenchymal progenitors and maintains mesenchymal stromal cells in an undifferentiated state  

PubMed Central

With the increasing use of culture-expanded mesenchymal stromal cells (MSCs) for cell therapies, factors that regulate the cellular characteristics of MSCs have been of major interest. Oxygen concentration has been shown to influence the functions of MSCs, as well as other normal and malignant stem cells. However, the underlying mechanisms of hypoxic responses and the precise role of hypoxia-inducible factor-1? (Hif-1?), the master regulatory protein of hypoxia, in MSCs remain unclear, due to the limited span of Hif-1? stabilization and the complex network of hypoxic responses. In this study, to further define the significance of Hif-1? in MSC function during their self-renewal and terminal differentiation, we established adult bone marrow (BM)-derived MSCs that are able to sustain high level expression of ubiquitin-resistant Hif-1? during such long-term biological processes. Using this model, we show that the stabilization of Hif-1? proteins exerts a selective influence on colony-forming mesenchymal progenitors promoting their self-renewal and proliferation, without affecting the proliferation of the MSC mass population. Moreover, Hif-1? stabilization in MSCs led to the induction of pluripotent genes (oct-4 and klf-4) and the inhibition of their terminal differentiation into osteogenic and adipogenic lineages. These results provide insights into the previously unrecognized roles of Hif-1? proteins in maintaining the primitive state of primary MSCs and on the cellular heterogeneities in hypoxic responses among MSC populations.

Park, In-Ho; Kim, Kwang-Ho; Choi, Hyun-Kyung; Shim, Jae-Seung; Whang, Soo-Young; June Hahn, Sang; Kwon, Oh-Joo; Oh, Il-Hoan

2013-01-01

164

Effect of mast cell granules on the gene expression of nitric oxide synthase and tumour necrosis factor-alpha in macrophages.  

PubMed Central

Previous studies have shown that mast cell granules (MCG) inhibit numerous macrophage functions including tumour cytotoxicity, superoxide and nitric oxide (NO) production, and FCgamma2a receptor-mediated phagocytosis. In this study, the effect of MCG on macrophage TNF alpha and nitric oxide synthase (iNOS) mRNA expression, and the production and fate of TNF alpha were examined. Upon activation with LPS+IFN gamma, macrophages expressed both TNF alpha and iNOS mRNA and produced both TNF alpha and NO. Co-incubation of LPS+IFN gamma-activated macrophages with MCG resulted in dose-dependent inhibition of iNOS mRNA expression. TNF alpha production in the activated macrophages was decreased by MCG, which was associated with a reduction in TNF alpha mRNA expression. MCG were also capable of degrading both macrophage-generated and recombinant TNF alpha. The direct effect of MCG on TNF alpha was partially reversed by a mixture of protease inhibitors. These results demonstrate that MCG decrease the production of NO and TNF alpha by inhibiting macrophage iNOS and TNF alpha gene expression. Furthermore, MCG post-transcriptionally alter TNF alpha levels via proteolytic degradation.

Li, Y; Nguyen, T D; Stechschulte, A C; Stechschulte, D J; Dileepan, K N

1998-01-01

165

Signaling pathways mediating a selective induction of nitric oxide synthase II by tumor necrosis factor alpha in nerve growth factor-responsive cells  

Microsoft Academic Search

BACKGROUND: Inflammation and oxidative stress play a critical role in neurodegeneration associated with acute and chronic insults of the nervous system. Notably, affected neurons are often responsive to and dependent on trophic factors such as nerve growth factor (NGF). We previously showed in NGF-responsive PC12 cells that tumor necrosis factor alpha (TNF?) and NGF synergistically induce the expression of the

Michael S Thomas; WenRu Zhang; Paivi M Jordan; H Uri Saragovi; Giulio Taglialatela

2005-01-01

166

IN VITRO REGULATION OF MAC-1 EXPRESSION ON BOVINE POLYMORPHONUCLEAR LEUKOCYTES BY ENDOTOXIN AND TUMOR NECROSIS FACTOR-ALPHA AT DIFFERENT STAGES OF LACTATION  

Technology Transfer Automated Retrieval System (TEKTRAN)

This study intends to clarify some of the underlying mechanisms leading to the increased susceptibility of dairy cows to periparturient diseases, such as coliform mastitis. Surface expression of the adhesion molecule Mac-1 (CD11b, CR3) on PMN and of CD14 on monocytes was measured in early (EL), peak...

167

TERATOGENIC EFFECTS OF RETINOIC ACID ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR AND TRANSFORMING GROWTH FACTOR-ALPHA  

EPA Science Inventory

Background: EGF and TGF regulate cell proliferation and differentiation in the embryo. The induction of cleft palate (CP) by all trans retinoic acid (RA) was associated with altered expression of TGF, EGF receptor and binding of EGF. The present study uses knockout (KO) mice to e...

168

Babesia bovis-Stimulated Macrophages Express Interleukin1beta , Interleukin12, Tumor Necrosis Factor Alpha, and Nitric Oxide and Inhibit Parasite Replication In Vitro  

Microsoft Academic Search

The tick-transmitted hemoparasite Babesia bovis causes an acute infection that results in persistence and immunity against challenge infection in cattle that control the initial parasitemia. Resolution of acute infection with this protozoal pathogen is believed to be dependent on products of activated macrophages (Mf), including inflammatory cytokines and nitric oxide (NO) and its derivatives. B. bovis stimulates inducible nitric oxide

LISL K. M. SHODA; GUY H. PALMER; JORGE FLORIN-CHRISTENSEN; MONICA FLORIN-CHRISTENSEN; DALE L. GODSON; WENDY C. BROWN

2000-01-01

169

Expression of epidermal growth factor, epidermal growth factor receptor and transforming growth factor-alpha in the human fetal inner ear  

Microsoft Academic Search

The expression of epidermal growth factor (EGF), EGF receptor and transforming growth factor (TGF)-alpha was analyzed in the human fetal inner ear using immuno-histochemical methods. EGF receptor was observed only in 9.5-week-old fetal vestibular epithelia. In 14- and 16-week-old fetuses, EGF receptor could not be detected. TGF-alpha was observed strongly in the 9- and 11-week-old vestibular epithelia, whereas only trace

H. Yamashita; M. Takahashi; D. Bagger-Sjöbäck

1996-01-01

170

Chronic Neuron-Specific Tumor Necrosis Factor-Alpha Expression Enhances the Local Inflammatory Environment Ultimately Leading to Neuronal Death in 3xTg-AD Mice  

PubMed Central

Inflammatory mediators, such as tumor necrosis factor-? (TNF-?) and interleukin-1beta, appear integral in initiating and/or propagating Alzheimer’s disease (AD)-associated pathogenesis. We have previously observed a significant increase in the number of mRNA transcripts encoding the pro-inflammatory cytokine TNF-?, which correlated to regionally enhanced microglial activation in the brains of triple transgenic mice (3xTg-AD) before the onset of overt amyloid pathology. In this study, we reveal that neurons serve as significant sources of TNF-? in 3xTg-AD mice. To further define the role of neuronally derived TNF-? during early AD-like pathology, a recombinant adeno-associated virus vector expressing TNF-? was stereotactically delivered to 2-month-old 3xTg-AD mice and non-transgenic control mice to produce sustained focal cytokine expression. At 6 months of age, 3xTg-AD mice exhibited evidence of enhanced intracellular levels of amyloid-? and hyperphosphorylated tau, as well as microglial activation. At 12 months of age, both TNF receptor II and Jun-related mRNA levels were significantly enhanced, and peripheral cell infiltration and neuronal death were observed in 3xTg-AD mice, but not in non-transgenic mice. These data indicate that a pathological interaction exists between TNF-? and the AD-related transgene products in the brains of 3xTg-AD mice. Results presented here suggest that chronic neuronal TNF-? expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-?-specific agents to subvert AD.

Janelsins, Michelle C.; Mastrangelo, Michael A.; Park, Keigan M.; Sudol, Kelly L.; Narrow, Wade C.; Oddo, Salvatore; LaFerla, Frank M.; Callahan, Linda M.; Federoff, Howard J.; Bowers, William J.

2008-01-01

171

Expression of tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase-3 in proliferated synovium in a patient with synovitis-acne-pustulosis-hyperostosis-osteitis syndrome: a case report  

PubMed Central

Introduction Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is a rare disorder. The etiology remains unknown and the treatment is still empirical. Synovitis is one of the major manifestations, but information on histopathological features is still lacking. In this case, we investigated the histopathological features of SAPHO syndrome synovitis. Case presentation We present the case of a 53-year-old Japanese woman with SAPHO syndrome accompanied by marked knee synovitis and palmoplantar pustulosis. We found abundant sterile joint fluid in the right knee, and a blood test showed abnormally high values of C-reactive protein (17.26 mg/dl) and matrix metalloproteinase-3 (800 ng/ml). Arthroscopic surgery revealed marked proliferation of villous synovial tissues similar to rheumatoid arthritis and standard microscopic findings were also similar to rheumatoid arthritis. Furthermore, for the first time, we demonstrated by immunohistochemistry the expression of tumor necrosis factor-alpha (TNF-?) converting enzyme, TNF-? and matrix metalloproteinase-3 in the proliferated synovial lining cells. After arthroscopic synovectomy, her knee symptoms immediately diminished and laboratory data (matrix metalloproteinase-3 and C-reactive protein) normalized within 2 weeks of surgery. Conclusion We demonstrate the expression of TNF-? converting enzyme, TNF-? and matrix metalloproteinase-3 in SAPHO syndrome synovitis for the first time and also show, both macro- and microscopically, the similarity between SAPHO syndrome and rheumatoid arthritis synovitis. These new findings support the recently reported successful treatment of SAPHO syndrome with antirheumatic drugs, especially with anti-TNF-? agents.

2009-01-01

172

The epidermal growth factor receptor mediates tumor necrosis factor-alpha-induced activation of the ERK/GEF-H1/RhoA pathway in tubular epithelium.  

PubMed

Tumor necrosis factor (TNF)-? induces cytoskeleton and intercellular junction remodeling in tubular epithelial cells; the underlying mechanisms, however, are incompletely explored. We have previously shown that ERK-mediated stimulation of the RhoA GDP/GTP exchange factor GEF-H1/Lfc is critical for TNF-?-induced RhoA stimulation. Here we investigated the upstream mechanisms of ERK/GEF-H1 activation. Surprisingly, TNF-?-induced ERK and RhoA stimulation in tubular cells were prevented by epidermal growth factor receptor (EGFR) inhibition or silencing. TNF-? also enhanced phosphorylation of the EGFR. EGF treatment mimicked the effects of TNF-?, as it elicited potent, ERK-dependent GEF-H1 and RhoA activation. Moreover, EGF-induced RhoA activation was prevented by GEF-H1 silencing, indicating that GEF-H1 is a key downstream effector of the EGFR. The TNF-?-elicited EGFR, ERK, and RhoA stimulation were mediated by the TNF-? convertase enzyme (TACE) that can release EGFR ligands. Further, EGFR transactivation also required the tyrosine kinase Src, as Src inhibition prevented TNF-?-induced activation of the EGFR/ERK/GEF-H1/RhoA pathway. Importantly, a bromodeoxyuridine (BrdU) incorporation assay and electric cell substrate impedance-sensing (ECIS) measurements revealed that TNF-? stimulated cell growth in an EGFR-dependent manner. In contrast, TNF-?-induced NF?B activation was not prevented by EGFR or Src inhibition, suggesting that TNF-? exerts both EGFR-dependent and -independent effects. In summary, in the present study we show that the TNF-?-induced activation of the ERK/GEF-H1/RhoA pathway in tubular cells is mediated through Src- and TACE-dependent EGFR activation. Such a mechanism could couple inflammatory and proliferative stimuli and, thus, may play a key role in the regulation of wound healing and fibrogenesis. PMID:21212278

Kakiashvili, Eli; Dan, Qinghong; Vandermeer, Matthew; Zhang, Yuqian; Waheed, Faiza; Pham, Monica; Szászi, Katalin

2011-01-06

173

Heat shock protein 90 suppresses tumor necrosis factor alpha induced apoptosis by preventing the cleavage of Bid in NIH3T3 fibroblasts  

Microsoft Academic Search

Two highly conserved mechanisms for maintaining cellular homeostasis are apoptosis and the cellular stress response. Hsp90 is one of the most abundant, highly conserved, and inducible Hsps in eukaryotes. Recently, Hsp90 has been shown to play important antiapoptotic roles through binding with Apaf-1, RIP and kinase domain of IKK?\\/?. Our present studies demonstrate that Hsp90 can suppress tumor necrosis factor

Chen Zhao; Enhua Wang

2004-01-01

174

JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes.  

PubMed

Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3-L1 adipocytes with a mixture of free fatty acids (FFAs) to investigate the molecular mechanisms underlying fat-induced insulin resistance. FFA treatment impaired insulin receptor-mediated signal transduction and decreased insulin-stimulated GLUT4 translocation and glucose transport. FFAs activated the stress/inflammatory kinases c-Jun N-terminal kinase (JNK) and IKKbeta, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-alpha, and decreased secretion of adiponectin into the medium. RNA interference-mediated down-regulation of JNK blocked JNK activation and prevented most of the FFA-induced defects in insulin action. Blockade of TNF-alpha signaling with neutralizing antibodies to TNF-alpha or its receptors or with a dominant negative TNF-alpha peptide had a partial effect to inhibit FFA-induced cellular insulin resistance. We found that JNK activation by FFAs was not inhibited by blocking TNF-alpha signaling, whereas the FFA-induced increase in TNF-alpha secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-alpha-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-alpha is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance. PMID:16085647

Nguyen, M T Audrey; Satoh, Hiroaki; Favelyukis, Svetlana; Babendure, Jennie L; Imamura, Takeshi; Sbodio, Juan I; Zalevsky, Jonathan; Dahiyat, Bassil I; Chi, Nai-Wen; Olefsky, Jerrold M

2005-08-05

175

Processing of tumour necrosis factor-alpha precursor by metalloproteinases  

Microsoft Academic Search

TUMOUR necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and immunomodulatory cytokine implicated in inflammatory conditions such as rheumatoid arthritis, Crohn's disease, multiple sclerosis and the cachexia associated with cancer or human immunodeficiency virus infection1. TNF-alpha is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine2. The processing enzyme(s) which cleave TNF-alpha are

A. J. H. Gearing; P. Beckett; M. Christodoulou; M. Churchill; J. Clements; A. H. Davidson; A. H. Drummond; W. A. Galloway; R. Gilbert; J. L. Gordon; T. M. Leber; M. Mangan; K. Miller; P. Nayee; K. Owen; S. Patel; W. Thomas; G. Wells; L. M. Wood; K. Woolley

1994-01-01

176

Temporal correlation of tumor necrosis factor-alpha release, upregulation of pulmonary ICAM-1 and VCAM-1, neutrophil sequestration, and lung injury in diet-induced pancreatitis  

Microsoft Academic Search

Lung injury is a major cause of patient morbidity in acute pancreatitis. The purpose of this study was to examine the mechanism\\u000a of pulmonary infiltration and lung injury in acute pancreatitis. Mice were fed a choline-deficient\\/ethionine-supplemented\\u000a (CDE) diet for 144 hours to induce severe acute pancreatitis. Serum samples were collected for measurement of biochemical\\u000a markers of disease and for the

Andrew H. Lundberg; D. Neil Granger; Janice Russell; Scott Callicutt; Lillian W. Gaber; Malak Kotb; Omaima Sabek; A. Osama Gaber

2000-01-01

177

Correlation between Sustained c-Jun N-terminal Protein Kinase Activation and Apoptosis Induced by Tumor Necrosis Factor-alpha in Rat Mesangial Cells  

Microsoft Academic Search

Rat mesangial cells are normally resistant to tumor necrosis factor-a (TNF-a)-induced apoptosis. In this re- port we show that the cells can be made susceptible to the apoptotic effect of TNF-a when pretreated with ac- tinomycin D, cycloheximide, or vanadate. c-Jun N-ter- minal protein kinase (JNK) has been thought to mediate apoptotic processes elicited by some stimuli, but its in-

Yan-Lin Guo; Kemal Baysal; Baobin Kang; Li-Jun Yang; John R. Williamson

1998-01-01

178

Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha.  

PubMed

Remodeling of the airways, as occurs in asthmatic patients, is associated with the continual presence of inflammatory mediators and Th2 cytokines, especially interleukin (IL)-13, during cycles of epithelial injury and repair. In this study, we examined the effect of IL-13 on well-differentiated normal human bronchial epithelial (NHBE) cells maintained in air-liquid interface culture. IL-13 induced proliferation of NHBE cells after 24 h exposure, as reflected by [(3)H]thymidine uptake and cell counts. The effects of IL-13 were mediated through the epidermal growth factor receptor (EGFR), as proliferation was attenuated by AG1478, an EGFR tyrosine kinase inhibitor. Proliferation appeared to be mediated by transforming growth factor (TGF)-alpha, a potent ligand for EGFR, which was released rapidly from NHBE cells in response to IL-13. Neutralizing antibody to TGF-alpha, but not antibodies against other potentially important growth factors (EGF, heparin binding epidermal growth factor-like growth factor [HB-EGF], platelet-derived growth factor [PDGF]), inhibited the mitogenic response to IL-13. This study provides the first experimental evidence that IL-13 can initiate a proliferative response of human airway epithelium in the absence of inflammatory cells or other cell types. The results are consistent with a mechanism whereby IL-13 induces release of TGF-alpha from the epithelial cells, which in turn binds via an autocrine/paracrine-type action to the EGFR, initiating proliferation. IL-13-induced airway remodeling in vivo may involve this epithelium-driven response. PMID:11726400

Booth, B W; Adler, K B; Bonner, J C; Tournier, F; Martin, L D

2001-12-01

179

Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism.  

PubMed Central

Human cytomegalovirus (HCMV) is a potential cofactor in HIV-1 infection. To investigate the mechanism whereby HCMV promotes HIV-1 replication, a PBMC coculture assay which measures HIV-1 p24 antigen release was used as an index of viral replication. HCMV-stimulated PBMC were capable of inducing HIV-1 replication in cocultures with acutely infected PBMC; however, this occurred only when the PBMC were from HCMV-seropositive donors (598 +/- 207 versus 27 +/- 10 pg/ml p24 antigen with PBMC from HCMV-seronegative donors on day 6 of coculture). Upon stimulation with HCMV, PBMC obtained exclusively from HCMV-seropositive donors released tumor necrosis factor (TNF)-alpha (270 +/- 79 pg/ml at 18 h of culture). Monoclonal antibodies to TNF-alpha blocked the activity of HCMV-stimulated PBMC in cocultures both with acutely HIV-1-infected PBMC and with the chronically infected promonocytic line U1. Also, treatment of HCMV-stimulated PBMC with pentoxifylline, an inhibitor of TNF-alpha mRNA, markedly reduced HIV-1 replication in cocultures both with acutely and chronically infected cells. These results indicate that TNF-alpha is a key mediator of HIV-1 replication induced by HCMV-stimulated PBMC and support the concept that this cytokine plays an important role in the pathogenesis of HIV-1 infection.

Peterson, P K; Gekker, G; Chao, C C; Hu, S X; Edelman, C; Balfour, H H; Verhoef, J

1992-01-01

180

Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum  

PubMed Central

Previous studies have demonstrated the presence of myocardial depression in clinical and experimental septic shock. This depression is associated with the presence of a circulating myocardial depressant substance with physical characteristics consistent with cytokines. The present study utilized an in vitro myocardial cell assay to examine the role of various human recombinant cytokines, including tumor necrosis factor (TNF)alpha and interleukin (IL)1beta, in depression of cardiac myocyte contractile function induced by serum from humans with septic shock. The extent and velocity of electrically paced rat cardiac myocytes in tissue culture was quantified by a closed loop video tracking system. Individually, TNF-alpha and IL-1beta each caused significant concentration-dependent depression of maximum extent and peak velocity of myocyte shortening in vitro. In combination, TNF-alpha and IL-1beta induced depression of myocardial cell contractility at substantially lower concentrations consistent with a synergistic effect. Using immunoabsorption, removal of both TNF-alpha and IL-1beta (but not either alone) from the serum of five patients with acute septic shock and marked reversible myocardial depression resulted in elimination of serum myocardial depressant activity. IL-2, -4, -6, -8, - 10, and interferon gamma failed to cause significant cardiac myocyte depression over a wide range of concentrations. These data demonstrate that TNF-alpha and IL-1beta cause depression of myocardial cell contraction in vitro and suggest that these two cytokines act synergistically to cause sepsis-associated myocardial depression in humans.

1996-01-01

181

Induced autocrine signaling through the epidermal growth factor receptor contributes to the response of mammary epithelial cells to tumor necrosis factor alpha  

SciTech Connect

In contrast to the well-known cytotoxic effects of tumor necrosis factor a (TNF) in many mammary cancer cells, we have found that TNF stimulates the proliferation and motility of human mammary epithelial cells (HMEC). Since the response of HMEC to TNF is similar to effects mediated by epidermal growth factor receptor (EGFR) activation, we explored the potential role of cross-talk through the EGFR signaling pathways in mediating cellular responses to TNF. Using a microarray enzyme-linked immunoassay, we found that exposure to TNF stimulated the dose-dependent shedding of the EGFR ligand transforming growth factor a (TGFa). Both proliferation and motility of HMEC induced by TNF was prevented either by inhibiting membrane protein shedding with a metalloprotease inhibitor, by blocking EGFR kinase activity, or by limiting ligand-receptor interactions with an antagonistic anti-EGFR antibody. EGFR activity was also necessary for TNF-induced release of MMP-9, a matrix metalloprotease thought to be an essential regulator of mammary cell migration. The cellular response to TNF was associated with a biphasic temporal pattern of extracellular signal-regulated kinase (ERK) phosphorylation, which was EGFR-dependent and modulated by inhibition of metalloprotease-mediated shedding. Significantly, the late phase of ERK phosphorylation, detectable within 4 hours after exposure, was blocked by the metalloprotease inhibitor batimastat, indicating that autocrine signaling through ligand shedding was responsible for this secondary wave of ERK activity. Our results indicate a novel and important role for metalloprotease activation and EGFR transmodulation in mediating the cellular response to TNF.

Chen, Wan-Nan U.; Woodbury, Ronald L.; Kathmann, Loel E.; Opresko, Lee; Zangar, Richard C.; Wiley, H S.; Thrall, Brian D.

2004-04-30

182

14-Deoxyandrographolide desensitizes hepatocytes to tumour necrosis factor-alpha-induced apoptosis through calcium-dependent tumour necrosis factor receptor superfamily member 1A release via the NO/cGMP pathway  

PubMed Central

BACKGROUND AND PURPOSE Andrographis paniculata (AP) has been found to display hepatoprotective effect, although the mechanism of action of the active compounds of AP in this context still remains unclear. Here, we evaluated the hepatoprotective efficacy of 14-deoxyandrographolide (14-DAG), a bioactive compound of AP, particularly its role in desensitization of hepatocytes to tumour necrosis factor-alpha (TNF-?)-induced signalling of apoptosis. EXPERIMENTAL APPROACH TNF-?-mediated ligand receptor interaction in hepatocytes in the presence of 14-DAG was studied in vitro in primary hepatocyte cultures, with the help of co-immunoprecipitation, confocal microscopy and FACS analysis. Events associated with 14-DAG-induced TNFRSF1A release from hepatocytes were determined using immunoblotting, biochemical assay and fluorimetric studies. Pulse-chase experiments with radiolabelled TNF-? and detection of apoptotic nuclei by terminal transferase-mediated dUTP nick-end labelling were performed under in vivo conditions. KEY RESULTS 14-DAG down-regulated the formation of death-inducing signalling complex, resulting in desensitization of hepatocytes to TNF-?-induced apoptosis. Pretreatment of hepatocytes with 14-DAG accentuated microsomal Ca-ATPase activity through induction of NO/cGMP pathway. This resulted in enhanced calcium influx into microsomal lumen with the formation of TNFRSF1A–ARTS-1–NUCB2 complex in cellular vesicles. It was followed by the release of full-length 55 kDa TNFRSF1A and a reduction in the number of cell surface TNFRSF1A, which eventually caused diminution of TNF-? signal in hepatocytes. CONCLUSION AND IMPLICATION Taken together, the results demonstrate for the first time that 14-DAG desensitizes hepatocytes to TNF-?-mediated apoptosis through the release of TNFRSF1A. This can be used as a strategy against cytokine-mediated hepatocyte apoptosis in liver dysfunctions.

Roy, DN; Mandal, S; Sen, G; Mukhopadhyay, S; Biswas, T

2010-01-01

183

Transforming Growth Factor ?1 Genotypes in Relation to TGF?1, Interleukin-8, and Tumor Necrosis Factor Alpha in Induced Sputum and Blood in Cystic Fibrosis  

PubMed Central

Background. High-producer TGF?1 genotypes are associated with severe lung disease in cystic fibrosis (CF), but studies combining IL-8, TNF?-, and TGF?1(+genotype) levels and their impact on CF lung disease are scarce. Aim. Assessing the relationship between TGF?1, IL-8, and TNF-? and lung disease in CF in an exacerbation-free interval. Methods. Twenty four patients delta F508 homozygous (median age 20.5?y, Shwachman score 75, FEV1(%) 83) and 8 controls (median age 27.5?y) were examined. TGF?1 was assessed in serum and induced sputum (IS) by ELISA, for IL-8 and TNF-? by chemiluminescence in IS and whole blood. Genotyping was performed for TGF?1 C?509T and T+869C utilizing RFLP. Results. TGF?1 in IS (CF/controls median 76.5/59.1?pg/mL, P < 0.074) was higher in CF. There was a negative correlation between TGF?1 in serum and lung function (LF) (FEV1 (r = ?0.488, P = 0.025), MEF 25 (r = ?0.425, P = 0.055), and VC (r = ?0.572, P = 0.007)). Genotypes had no impact on TGF?1 in IS, serum, and LF. In IS TGF?1 correlated with IL-8 (r = 0.593, P < 0.007) and TNF-? (r = 0.536, P < 0.018) in patients colonized by bacteria with flagellin. Conclusion. TGF?1 in serum not in IS correlates with LF. In patients colonized by bacteria with flagellin, TGF?1 correlates with IL-8 and TNF-? in IS.

Eickmeier, O.; Boom, L. v. d.; Schreiner, F.; Lentze, M. J.; NGampolo, D.; Schubert, R.; Zielen, S.; Schmitt-Grohe, S.

2013-01-01

184

Absence of tumor necrosis factor alpha, interleukin-6 (IL-6), and granulocyte-macrophage colony-stimulating factor expression but presence of IL-1beta, IL-8, and IL-10 expression in human monocytes exposed to viable or killed Ehrlichia chaffeensis.  

PubMed Central

Ehrlichia chaffeensis is a recently isolated minute gram-negative obligatory intracellular bacterium of monocytes/macrophages and is the etiologic agent of human monocytic ehrlichiosis. It is not known how macrophages respond when they encounter ehrlichiae in terms of cytokine production. In this study, we examined cytokine mRNA expression by incubating E. chaffeensis with THP-1 cells and performing competitive reverse transcription-PCR (RT-PCR). At 2 h postinfection, the levels of interleukin-1beta (IL-1beta), IL-8, and IL-10 mRNAs were significant but lower than those following Escherichia coli lipopolysaccharide (LPS) stimulation. Unlike the situation with E. coli LPS stimulation, however, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha) mRNAs were not induced. Time course and dose-response studies confirmed the absence of IL-6, GM-CSF, and TNF-alpha mRNA induction with E. chaffeensis. Viable E. chaffeensis organisms were not required for IL-1beta IO, IL-8, and IL-10 mRNA induction, since heat-killed E. chaffeensis induced identical time course responses. IL-1beta, IL-8, and IL-10 mRNAs were detected for up to 21, 21, and 24 h postexposure with E. chaffeensis, respectively, which were shut off more rapidly than with LPS stimulation. Although heat treatment of E. chaffeensis had no effect, periodate treatment completely abolished the ability of E. chaffeensis to induce IL-1beta, IL-8, and IL-10 mRNAs. The capture enzyme-linked immunosorbent assay result corresponded with the RT-PCR results, showing that viable and heat-killed E. chaffeensis produced and secreted the same levels of IL-1beta and IL-8. IL-10 production was significantly reduced by heat treatment. Periodate-treated ehrlichiae did not induce production of any of the cytokines tested. Anti-CD14 monoclonal antibody and polymyxin B did not inhibit IL-1beta mRNA expression upon exposure to E. chaffeensis. The absence of TNF-alpha, IL-6, and GM-CSF mRNA induction may delay the development of a protective immune response, thereby allowing E. chaffeensis to set up residence in macrophages.

Lee, E H; Rikihisa, Y

1996-01-01

185

Matrix Metalloproteinase 9 (MMP9) Expression in Preeclamptic Decidua and MMP9 Induction by Tumor Necrosis Factor Alpha and Interleukin 1 Beta in Human First Trimester Decidual Cells1  

PubMed Central

Extravillous trophoblasts (EVTs) invade human decidua via sequential integrin-mediated binding and proteolysis of basement membrane proteins in the extracellular matrix (ECM). In preeclampsia, shallow EVT invasion impairs spiral artery and arteriole remodeling to reduce uteroplacental blood flow. Excess decidual cell-expressed matrix metalloproteinases (MMPs) 2 and 9, in response to preeclampsia-related interleukin 1 beta (IL1B) and tumor necrosis factor alpha (TNF), may inappropriately degrade these basement membrane proteins and impede EVT invasion. This study found significantly higher immunohistochemical MMP9 levels in decidual cells and adjacent interstitial trophoblasts in placental sections of preeclamptic versus gestational age-matched control women. In contrast, immunostaining for MMP2 and tissue inhibitor of matrix metalloproteinases 1 and 2 (TIMP1 and TIMP2) were similar in preeclamptic and control groups. First-trimester decidual cells were incubated with estradiol (E2) or E2 + medroxyprogesterone acetate (MPA), with or without TNF or IL1B. As measured by ELISA, both cytokines elicited concentration-dependent increases in secreted MMP9 levels that were unaffected by MPA. In contrast, secreted levels of MMP2, TIMP1, and TIMP2 were unchanged in all treatment groups. Substrate gel zymography and Western blotting confirmed that each cytokine increased secreted levels of MMP9 but not MMP2. Similarly, quantitative RT-PCR found that TNF and IL1B enhanced MMP9, but not MMP2, mRNA levels. At the implantation site, inflammatory cytokine-enhanced MMP9 may promote preeclampsia by disrupting the decidual ECM to interfere with normal stepwise EVT invasion.

Lockwood, Charles J.; Oner, Ceyda; Uz, Yesim H.; Kayisli, Umit A.; Huang, S. Joseph; Buchwalder, Lynn F.; Murk, William; Funai, Edmund F.; Schatz, Frederick

2011-01-01

186

Immunoneutralization of transforming growth factor alpha present in bovine follicular fluid prevents the suppression of the follicle-stimulating hormone-induced production of estradiol by bovine granulosa cells cultured in vitro.  

PubMed

Growth factors such as transforming growth factors alpha (TGF alpha) and beta (TGFbeta) secreted by theca cells and present in bovine follicular fluid (bFF) have been implicated in granulosa cell growth and differentiation. We investigated these phenomena using two complementary approaches to evaluate the physiological contribution of TGF alpha and TGFbeta in the control of the FSH-induced estradiol production in bovine granulosa cells from large follicles. Granulosa cells (3 x 10(5) viable cells/cm2) harvested from eCG-treated prepubertal calves were cultured (serum free) in wells containing 500 microl/cm2 of defined Ham's F-12 medium supplemented with 0.5 ng/ml FSH for the first 3 days (37 degrees C; 95% air:5% CO2). In the first approach, the effects of individual addition of TGF alpha and TGFbeta at final concentrations of 1 x 10(-4) to 10 ng/ml were determined on Day 4 of culture after stimulation of granulosa cell estradiol production with 6 ng/ml FSH. In a second approach, TGF alpha or TGFbeta was removed specifically from bFF (from large follicles > 10 mm) by immunoneutralization. Thereafter, effects of immunoneutralization of TGF alpha or TGFbeta (0, 0.1, 1, 10, and 100 microg/ml anti-TGF neutralizing antibody) present in bFF (2%) were determined on Day 4 of culture following stimulation of granulosa cell estradiol production with 6 ng/ml FSH. On Day 4, FSH increased (p < 0.001) granulosa cell estradiol production (0 vs. 6 ng/ml FSH). Addition of TGF alpha decreased the granulosa cell estradiol production after 6 ng/ml FSH stimulation in a dose-dependent manner (p < 0.001). In contrast, addition of TGFbeta had no effect on the granulosa cell estradiol production (p > 0.1) after the addition of 6 ng/ml FSH. Addition of bFF (2%) decreased (p < 0.0001) the FSH-induced estradiol production by bovine granulosa cells. After immunoneutralization of TGF alpha in bFF, however, this suppressed FSH-induced estradiol production was restored to levels obtained in the absence of bFF, and this occurred in a dose-dependent manner (p < 0.05). Immunoneutralization of TGFbeta in bFF did not prevent (p > 0.1) the suppressive effect of bFF on FSH-induced estradiol production. These results suggest that TGF alpha produced in vivo by large bovine follicles can act locally (auto/paracrine manner) to suppress granulosa cell estradiol production. PMID:9241048

Rouillier, P; Sirard, M A; Matton, P; Guilbault, L A

1997-08-01

187

Pathogenesis of experimental neonatal woodchuck hepatitis virus infection: Chronicity as an outcome of infection is associated with a diminished acute hepatitis that is temporally deficient for the expression of interferon gamma and tumor necrosis factor-alpha messenger RNAs  

Microsoft Academic Search

Surgical biopsies of the liver were obtained from woodchuck hepatitis virus (WHV)-infected neonatal woodchucks at 2 time points before the self-limited or chronic outcomes became obvious by serologic criteria. Following segregation of outcomes, livers were analyzed for intrahepatic type 1 cytokine messenger RNAs (mRNAs) (interleukin 2 [IL-2], interferon gamma [IFN-?], tumor necrosis factor-alpha [TNF-?]) and leukocyte inflammatory phenotype (IgG+ plasma

Ikuo Nakamura; James T. Nupp; Matthew Cowlen; William C. Hall; Bud C. Tennant; John L. Casey; John L. Gerin; Paul J. Cote

2001-01-01

188

Regulation of production of tumor necrosis factor alpha in monocytes stimulated by the 30-kilodalton antigen of Mycobacterium tuberculosis.  

PubMed Central

The 30-kDa secreted antigen of Mycobacterium tuberculosis was a strong inducer of tumor necrosis factor alpha in human monocytes. Our findings suggest that tumor necrosis factor alpha production may be up-regulated at both the posttranscriptional and transcriptional levels. Regulation at the posttranscriptional level probably reflects enhanced translational efficiency.

Averill, L; Toossi, Z; Aung, H; Boom, W H; Ellner, J J

1995-01-01

189

The role of glucagon-like peptide-2 on apoptosis, cell proliferation, and oxidant–antioxidant system at a mouse model of intestinal injury induced by tumor necrosis factor-alpha\\/actinomycin D  

Microsoft Academic Search

Tumor necrosis factor-alpha (TNF-?) is a multifunctional cytokine, which has the ability to produce cytotoxicity via induction\\u000a of cell death and cell cycle arrest. Blocking the synthesis of protective proteins through a transcriptional inhibitor such\\u000a as actinomycin D (Act D) sensitizes many cell types to TNF-? toxicity. Teduglutide, h[Gly2]GLP-2, is a protease-resistant synthetic analog of glucagon-like peptide-2 (GLP-2) which is

Pelin Arda-Pirincci; Sehnaz Bolkent

2011-01-01

190

Human T lymphocyte virus type I-induced myeloneuropathy in rats: implication of local activation of the pX and tumor necrosis factor-alpha genes in pathogenesis.  

PubMed

The pathogenetic roles of human T lymphocyte virus type I (HTLV-I) and cytokines were investigated in HTLV-I-induced myeloneuropathy in Wistar-King-Aptekman-Hokudai rats. In the nervous system, pX messenger RNAs of HTLV-I were selectively expressed in the diseased spinal cord and peripheral nerves but not in the unaffected cerebrum and cerebellum, even though proviral DNAs were consistently identified in these tissues. Among several cytokines examined, mRNA expression and production of tumor necrosis factor (TNF)-alpha in the spinal cord and cerebrospinal fluid correlated positively with the development of spinal cord lesions. The collective evidence strongly suggests that selective activation of HTLV-I, in particular Tax expression and production of TNF-alpha induced by HTLV-I infection in target spinal cord and peripheral nerves, is causally related to apoptotic death of oligodendrocytes and Schwann cells, a major pathogenetic pathway of the HTLV-I-induced myeloneuropathy. PMID:8699061

Tomaru, U; Ikeda, H; Ohya, O; Abe, M; Kasai, T; Yamasita, I; Morita, K; Wakisaka, A; Yoshiki, T

1996-08-01

191

Glucocorticoids Regulate Tristetraprolin Synthesis and Posttranscriptionally Regulate Tumor Necrosis Factor Alpha Inflammatory Signaling?  

PubMed Central

Glucocorticoids are used to treat various inflammatory disorders, but the mechanisms underlying these actions are incompletely understood. The zinc finger protein tristetraprolin (TTP) destabilizes several proinflammatory cytokine mRNAs by binding to AU-rich elements within their 3? untranslated regions, targeting them for degradation. Here we report that glucocorticoids induce the synthesis of TTP mRNA and protein in A549 lung epithelial cells and in rat tissues. Dexamethasone treatment leads to a sustained induction of TTP mRNA expression that is abrogated by RU486. Glucocorticoid induction of TTP mRNA is also blocked by actinomycin D but not by cycloheximide, suggesting a transcriptional mechanism which has been confirmed by transcription run-on experiments. The most widely characterized TTP-regulated gene is the AU-rich tumor necrosis factor alpha (TNF-?) gene. Dexamethasone represses TNF-? mRNA in A549 cells and decreases luciferase expression of a TNF-? 3? untranslated region reporter plasmid in an orientation-dependent manner. Small interfering RNAs to TTP significantly prevent this effect, and a cell line stably expressing a short-hairpin RNA to TTP conclusively establishes that TTP is critical for dexamethasone inhibition of TNF-? mRNA expression. These studies provide the molecular evidence for glucocorticoid regulation of human TTP and reflect a novel inductive anti-inflammatory signaling pathway for glucocorticoids that acts via posttranscriptional mechanisms.

Smoak, Kathleen; Cidlowski, John A.

2006-01-01

192

Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL6, IL8, and cell proliferation in synovium from patients with rheumatoid arthritis  

Microsoft Academic Search

Human six-transmembrane epithelial antigen of prostate4 (STEAP4), an ortholog of mouse tumor necrosis factor-?-induced adipose-related\\u000a protein (TIARP), plays a role in tumor necrosis factor (TNF)-dependent arthritis models. However, its role in rheumatoid arthritis\\u000a (RA) is still obscure. This study explored such a role for STEAP4. The expressions of STEAP4, TNF?, and IL-6 were compared\\u000a in synovia of RA and osteoarthritis

Yoko Tanaka; Isao Matsumoto; Keiichi Iwanami; Asuka Inoue; Reiko Minami; Naoto Umeda; Akihiro Kanamori; Naoyuki Ochiai; Keiji Miyazawa; Makoto Sugihara; Taichi Hayashi; Daisuke Goto; Satoshi Ito; Takayuki Sumida

193

Tumour necrosis factor-alpha inhibitor-induced hepatic injury in patients with rheumatoid arthritis: two case reports and an analysis of the laboratory data from the Slovenian national biologicals registry.  

PubMed

Tumour necrosis factor-alpha (TNF-?) inhibitors are widely used in the management of patients with rheumatoid arthritis (RA) and spondylarthritides. However, TNF-? inhibition may lead to adverse events, including liver injury. The RA patients are frequently treated with several potentially hepatotoxic drugs concomitantly; hence, a causative link between TNF-? inhibitors and liver injury is usually difficult to establish. We report two cases of RA patients who developed histologically manifest liver injury shortly after the introduction of treatment with two different TNF-? inhibitors. Furthermore, we present the analysis of the laboratory data from the BioRx.si registry (the Slovenian national registry of rheumatologic patients treated with biologicals) and provide evidence that elevated levels of serum aminotransferase can be observed in patients treated with TNF-? inhibitors. Additionally, our analysis suggests no significant differences between the impact of adalimumab and etanercept on aminotransferase levels. Although the use of TNF-alpha inhibitors is safe and efficient, we suggest that continuous careful monitoring of aminotransferase levels in patients treated with these agents is probably warranted. PMID:22955878

Perdan-Pirkmajer, Katja; Ho?evar, Alojzija; Rotar, Ziga; Zibert, Janez; Marolt, Vera Ferlan; Gu?ev, Filip; Tomši?, Matija

2012-09-07

194

Fusobacterium nucleatum Infection of Colonic Cells Stimulates MUC2 Mucin and Tumor Necrosis Factor Alpha?  

PubMed Central

The etiology of inflammatory bowel disease is not completely known, but it is influenced by the presence of normal gut microflora as well as yet-unrecognized pathogens. The anaerobic, Gram-negative bacterial species Fusobacterium nucleatum is a common resident of the human mouth and gut and varies in its pathogenic potential. In this study, we demonstrate that highly invasive F. nucleatum isolates derived from the inflamed guts of Crohn's disease patients evoked significantly greater MUC2 and tumor necrosis factor alpha (TNF-?) gene expression than minimally invasive strains isolated from the noninflamed gut in human colonic epithelial cells and in a rat ligated colonic loop model of infection. Only live F. nucleatum induced mucin secretion and TNF-? expression in direct contact with and/or during invasion of colonic cells. In rat colons, mucin secretion was augmented in response to a highly invasive F. nucleatum isolate but was unaffected by treatment with a minimally invasive strain. Taken together, these studies reveal that F. nucleatum may represent a challenging pathogen in the etiology of gut inflammatory diseases and highlight the importance of different pathotypes of candidate bacterial species in disease pathogenesis.

Dharmani, Poonam; Strauss, Jaclyn; Ambrose, Christian; Allen-Vercoe, Emma; Chadee, Kris

2011-01-01

195

Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha  

PubMed Central

Tumor necrosis factor-alpha (TNF-?), a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-? is severely limited by its toxicity. Currently, TNF-? is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-?, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-?. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-? conjugate, scFv/TNF-? fusion proteins, and peptide/TNF-? fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-?-based therapeutics into clinical investigation.

Cai, Weibo; Kerner, Zachary J.; Hong, Hao; Sun, Jiangtao

2013-01-01

196

Tumor Necrosis Factor Alpha Gene ?376 Polymorphism and Susceptibility to Multiple Sclerosis: An Egyptian Study  

Microsoft Academic Search

Tumor necrosis factor alpha, a proinflammatory cytokine, plays an important role in the clinical activity of relapsing–remitting\\u000a multiple sclerosis and the development of progression. Dysregulation in the expression of tumor necrosis factor gene had been\\u000a suggested in the pathogenesis of multiple sclerosis. Our aim was to investigate the relationship between tumor necrosis factor\\u000a ??376 polymorphism with disease susceptibility and course

Mona Abd el Fattah Nada; Dalia Ahmed Labib

2011-01-01

197

Increased Expression of Interleukin5 (IL5), IL13, and Tumor Necrosis Factor Alpha Genes in Intestinal Lymph Cells of Sheep Selected for Enhanced Resistance to Nematodes during Infection with Trichostrongylus colubriformis  

Microsoft Academic Search

Cytokine gene expression in cells migrating in afferent and efferent intestinal lymph was monitored for extended time periods in individual sheep experimentally infected with the nematode Trichostrongylus colub- riformis. Animals from stable selection lines with increased levels of either genetic resistance (R) or suscep- tibility (S) to nematode infection were used. Genes for interleukin-5 (IL-5), IL-13, and tumor necrosis factor

Anton Pernthaner; Sally-Ann Cole; Lilian Morrison; Wayne R. Hein

2005-01-01

198

Tumor Necrosis Factor Alpha Enhances Antifungal Activities of Polymorphonuclear and Mononuclear Phagocytes against Aspergillus fumigatus  

Microsoft Academic Search

Invasive aspergillosis is a serious complication in immunocompromised patients. The effects of recombinant human tumor necrosis factor alpha (TNF-a) on antifungal activities of human neutrophils (polymorphonu- clear leukocytes (PMNs)), human monocytes (MNCs), and rabbit pulmonary alveolar macrophages (PAMs) against Aspergillus fumigatus were studied. The percentage of PMN-induced hyphal damage was increased after 30 min of incubation of PMNs with 0.1

EMMANUEL ROILIDES; ANASTASIA DIMITRIADOU-GEORGIADOU; TIN SEIN; ISAAC KADILTSOGLOU; THOMAS J. WALSH

1998-01-01

199

Production of tumor necrosis factor alpha in human leukocytes stimulated by Cryptococcus neoformans.  

PubMed Central

Tumor necrosis factor alpha (TNF-alpha) is a key mediator of inflammation and may promote human immunodeficiency virus replication in latently infected cells. Since cryptococcosis often is associated with aberrations in the host inflammatory response and occurs preferentially in persons with AIDS, we defined the conditions under which human leukocytes produce TNF-alpha when stimulated by Cryptococcus neoformans. Peripheral blood mononuclear cells (PBMC) produced comparable amounts of TNF-alpha following stimulation with C. neoformans and lipopolysaccharide. Detectable TNF-alpha release in response to C. neoformans occurred only when fungi with small-sized capsules were used and complement-sufficient serum was added. Fractionation of PBMC established that monocytes were the predominant source of TNF-alpha. TNF-alpha gene expression and release occurred significantly later in PBMC stimulated with C. neoformans than in PBMC stimulated with LPS. C. neoformans was also a potent inducer of TNF-alpha from freshly isolated bronchoalveolar macrophages (BAM). Upon in vitro culture, BAM and monocytes bound greater numbers of fungal cells, yet their capacity to produce TNF-alpha following cryptococcal stimulation declined by 74 to 100%. However, this decline was reversed if the BAM and monocytes were cultured with gamma interferon. These data establish that C. neoformans can potently stimulate TNF-alpha release from human leukocytes. However, several variables profoundly affected the amount of TNF-alpha released, including the type of leukocyte and its state of activation, the size of the cryptococcal capsule, and the availability of opsonins.

Levitz, S M; Tabuni, A; Kornfeld, H; Reardon, C C; Golenbock, D T

1994-01-01

200

Epidermal growth factor and transforming growth factor-alpha suppress HLA class II induction in human thyroid epithelial cells.  

PubMed Central

Inappropriate expression of HLA class II by human thyroid epithelial cells (thyrocytes) occurs in autoimmune thyroid diseases where it may contribute to the pathogenesis. Several substances have been found to induce or up-regulate thyrocyte HLA class II expression in vitro. The present investigations show that the induction of HLA class II in human thyrocytes cultured with interferon (IFN)-gamma can be partially suppressed by exposure of the thyrocytes to epidermal growth factor (EGF): this occurs when the thyrocytes are treated with the two reagents simultaneously and also when the exposure to EGF is before or after that with IFN-gamma. Concentrations of EGF at least as low as 0.1 ng/ml show this inhibitory effect, which can be over-ridden by very high concentrations of IFN-gamma. Thyrocyte HLA class II expression stimulated by thyroid-stimulating hormone (TSH) (in the presence or absence of IFN-gamma) is also suppressed by EGF. Transforming growth factor-alpha (TGF alpha), which is structurally related to EGF and interacts with the same cell surface receptor, has a similar inhibitory activity on the induction of thyrocyte HLA class II expression. The existence of substances which can down-regulate, as well as those which can up-regulate, thyrocyte HLA class II expression raises the possibility that the occurrence of such expression in vivo may be determined by the balance between factors with opposing modulatory effects.

Todd, I; Hammond, L J; James, R F; Feldmann, M; Bottazzo, G F

1990-01-01

201

Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta.  

PubMed Central

The regulation of type 1 plasminogen activator inhibitor (PAI-1) gene expression was studied in vivo employing a murine model system. Nuclease protection analysis revealed relatively high concentrations of PAI-1 mRNA in the aorta, adipose tissue, heart, and lungs of untreated CB6 (BalbC X C57B16) mice. Treatment of CB6 mice with LPS, TNF-alpha, or transforming growth factor-beta (TGF-beta) increased the steady-state levels of PAI-1 mRNA within 3 h in all tissues examined. However, the greatest responses to TGF-beta were observed in adipose tissue and the kidney, while LPS and TNF-alpha strongly stimulated PAI-1 gene expression in the liver, kidney, lung, and adrenals. In C3H/HeJ mice, which exhibit defective TNF-alpha release in response to LPS, the response of the PAI-1 gene to LPS was severely attenuated. However, injection of these mice with TNF-alpha increased PAI-1 mRNA in a tissue-specific pattern strikingly similar to that observed in LPS-treated CB6 mice. These results demonstrate that the PAI-1 gene is regulated in a complex and tissue-specific manner in vivo, and suggest a role for TNF-alpha in the response of the PAI-1 gene to sepsis. Images

Sawdey, M S; Loskutoff, D J

1991-01-01

202

Methyl ester of avenathramide-C inhibits tumor necrosis factor-alpha (TNF-alpha) and interlenkin-Ibeta(IL-beta)-induced NF-kappaB activation in endothelial cells  

Technology Transfer Automated Retrieval System (TEKTRAN)

Atherosclerosis is a chronic inflammatory disease accompanied by the expression of endothelial proinflammatory molecules. Avenanthramides (Avn) are polyphenols which are present exclusively in oats. We have reported the avenanthramide-enriched mixture extracted from oats significantly suppressed int...

203

Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice  

PubMed Central

Background Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by a temporal and spatial progression of beta-amyloid (A?) deposition, neurofibrillary tangle formation, and synaptic degeneration. Inflammatory processes have been implicated in initiating and/or propagating AD-associated pathology within the brain, as inflammatory cytokine expression and other markers of inflammation are pronounced in individuals with AD pathology. The current study examines whether inflammatory processes are evident early in the disease process in the 3xTg-AD mouse model and if regional differences in inflammatory profiles exist. Methods Coronal brain sections were used to identify A? in 2, 3, and 6-month 3xTg-AD and non-transgenic control mice. Quantitative real-time RT-PCR was performed on microdissected entorhinal cortex and hippocampus tissue of 2, 3, and 6-month 3xTg-AD and non-transgenic mice. Microglial/macrophage cell numbers were quantified using unbiased stereology in 3xTg-AD and non-transgenic entorhinal cortex and hippocampus containing sections. Results We observed human A? deposition at 3 months in 3xTg-AD mice which is enhanced by 6 months of age. Interestingly, we observed a 14.8-fold up-regulation of TNF-? and 10.8-fold up-regulation of MCP-1 in the entorhinal cortex of 3xTg-AD mice but no change was detected over time in the hippocampus or in either region of non-transgenic mice. Additionally, this increase correlated with a specific increase in F4/80-positive microglia and macrophages in 3xTg-AD entorhinal cortex. Conclusion Our data provide evidence for early induction of inflammatory processes in a model that develops amyloid and neurofibrillary tangle pathology. Additionally, our results link inflammatory processes within the entorhinal cortex, which represents one of the earliest AD-affected brain regions.

Janelsins, Michelle C; Mastrangelo, Michael A; Oddo, Salvatore; LaFerla, Frank M; Federoff, Howard J; Bowers, William J

2005-01-01

204

TUMOR NECROSIS FACTOR-ALPHA-MEDIATED PULMONARY ENDOTHELIAL BARRIER DYSFUNCTION  

Technology Transfer Automated Retrieval System (TEKTRAN)

The multifunctional cytokine, tumor necrosis factor-alpha (TNF- alpha), is released from host cells in response to diverse injurious stimuli and is elevated during acute lung injury. Increased levels of TNF-alpha are found in both the bloodstream and bronchoalveolar lavage fluid of experimental and...

205

Polymorphonuclear leukocytes as a significant source of tumor necrosis factor-alpha in endotoxin-challenged lung tissue.  

PubMed Central

The kinetic expression and potential cellular source of tumor necrosis factor-alpha (TNF-alpha) in lipopolysaccharide-(LPS) induced acute lung inflammation was investigated using a rat model by Northern blot analysis, in situ hybridization and immunohistochemistry. LPS induced a polymorphonuclear leukocyte infiltrate in the lung that peaked between 6 and 24 hours. TNF-alpha messenger (m)RNA was strongly induced by LPS in whole lung tissues shown by Northern analysis. Both alveolar macrophages and polymorphonuclear leukocytes (PMNs), purified from bronchoalveolar lavage fluids of LPS-treated rats, were shown to express TNF-alpha mRNA by Northern analysis. However, PMNs displayed several times more TNF-alpha mRNA, relative to actin mRNA, than alveolar macrophages at 6 and 12 hours. By in situ hybridization, most of the cells positive for TNF-alpha mRNA at 6 and 12 hours seemed to be PMNs located within the tissue near bronchioles or vessels. By immunohistochemistry, TNF-alpha protein was localized mainly to alveolar macrophages at early times (1 to 3 hours) after LPS challenge, and thereafter, PMNs seemed to be the predominant source of TNF-alpha protein as more than 90% of total intraalveolar positive cells at 6 and 12 hours were PMN. Thus, our data provide the first in vivo evidence that PMNs can serve as a significant source of TNF-alpha at sites of acute inflammation. Images Figure 2 Figure 3

Xing, Z.; Kirpalani, H.; Torry, D.; Jordana, M.; Gauldie, J.

1993-01-01

206

Investigation of the Susceptibility of Human Cell Lines to Bovine Herpesvirus 4 Infection: Demonstration that Human Cells Can Support a Nonpermissive Persistent Infection Which Protects Them against Tumor Necrosis Factor Alpha-Induced Apoptosis  

Microsoft Academic Search

Bovine herpesvirus 4 (BoHV-4) is a gammaherpesvirus that has a worldwide distribution in the population of cattle. Many factors make human contamination by BoHV-4 likely to occur. In this study, we performed in vitro experiments to assess the risk and the consequences of human infection by BoHV-4. First, by using a re- combinant BoHV-4 strain expressing enhanced green fluorescent protein

L. Gillet; F. Minner; B. Detry; F. Farnir; L. Willems; M. Lambot; E. Thiry; P.-P. Pastoret; F. Schynts; A. Vanderplasschen

2004-01-01

207

Elevated serum levels of tumor necrosis factor alpha in normal-weight women with polycystic ovary syndrome  

Microsoft Academic Search

Since an increase in tumor necrosis factor alpha (TNF?) expression has been associated with insulin resistance, this study was undertaken to determine the status of circulating TNF? and the relationship of TNF? with insulin levels, body weight, or both in women with polycystic ovary syndrome (PCOS). Fasting serum samples were analyzed in 34 subjects with PCOS, of whom 22 were

Frank Gonzalez; Kuldip Thusu; Ehad Abdel-Rahman; Anu Prabhala; Madonna Tomani; Paresh Dandona

1999-01-01

208

Cytokines modulate glucose transport in skeletal muscle by inducing the expression of inducible nitric oxide synthase.  

PubMed Central

The principal goal of the present study was to test the hypothesis that cytokines modulate glucose transport in skeletal muscle by increasing nitric oxide production. Cultured L6 skeletal muscle cells were incubated in the presence of tumour necrosis factor-alpha, interferon-gamma or lipopolysaccharide (LPS) alone or in combination for 24 h. Neither cytokines nor LPS alone induced NO production, as measured by nitrite concentrations in the medium. However, when used in combination, the two cytokines significantly stimulated NO production, and this effect was synergistically enhanced by the presence of LPS. Reverse transcriptase-PCR (RT-PCR) analysis revealed that NO release was associated with the induction of inducible (macrophage-type) NO synthase (iNOS). The increase in iNOS expression was confirmed at the protein level by Western-blot analysis and NADPH/diaphorase histochemical staining. Cytokines and LPS markedly increased basal glucose transport in L6 myocytes. Insulin also stimulated basal glucose transport, but significantly less in cells chronically exposed to cytokines/LPS. The sensitivity of L6 muscle cells to insulin-stimulated glucose transport was also significantly decreased by cytokines/LPS treatment. The NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME) inhibited nitrite production in cytokine/LPS-treated cells, and this prevented the increase in basal glucose transport and restored muscle cell responsiveness to insulin. Cytokines/LPS exposure significantly increased GLUT1 transporter protein levels but decreased GLUT4 expression in L6 cells. l-NAME treatment prevented the increase in GLUT1 protein content but failed to restore GLUT4 transporter levels. These results demonstrate that cytokines and LPS affect glucose transport and insulin action by inducing iNOS expression and NO production in skeletal muscle cells. The data further indicate that cytokines and LPS increase the expression of the GLUT1 transporter protein by an NO-dependent mechanism.

Bedard, S; Marcotte, B; Marette, A

1997-01-01

209

Effect of honey bee venom on microglial cells nitric oxide and tumor necrosis factor-alpha production stimulated by LPS.  

PubMed

Abnormal activation of microglial cells has been implicated in various neurodegenerative diseases. Results showed that venom (KBV) produced and purified in Korea regulated lipopolysaccharides (LPS)-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in the murine microglia, BV-2 cell line. The production of proinflammatory cytokines, NO, and TNF-alpha was examined by LPS in BV-2 cell. The effect of KBV on the expression of inducible nitric oxide synthase (iNOS) and TNF-alpha was investigated by Western blot and RT-PCR in LPS-stimulated BV-2 cells. KBV suppressed the NO, iNOS, and TNF-alpha production, and decreased the levels of iNOS and TNF-alpha mRNA. These results suggest that KBV has anti-inflammatory properties that inhibit iNOS and TNF-alpha expression. KBV could be useful in inhibiting the production of inflammatory cytokine and NO production in neurodegenerative diseases. Further studies on the pharmacological aspects of the individual components of KBV are recommended. PMID:17166679

Han, SangMi; Lee, KwangGill; Yeo, JooHong; Kweon, HaeYong; Woo, SoonOk; Lee, MyeongLyeol; Baek, HaJu; Kim, SunYeou; Park, KwanKyu

2006-11-15

210

Pseudomonas aeruginosa Exoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines  

PubMed Central

Pseudomonas aeruginosa infection of cystic fibrosis patients causes lung damage that is substantially orchestrated by cytokines. In this study, multi-gene probe analysis was used to characterize the ability of the P. aeruginosa mitogen, exoenzyme S, to induce proinflammatory and immunoregulatory cytokines and chemokines. Exoenzyme S strongly induced transcription of proinflammatory cytokines and chemokines (tumor necrosis factor alpha, interleukin-1? [IL-1?], IL-1?, IL-6, IL-8, MIP-1?, MIP-1?, MCP-1, RANTES, and I-309), modest transcription of immunoregulatory cytokines (IL-10 and IL-12p40), and weak transcription of Th1 cytokines (IL-2 and gamma interferon). The response occurred early and subsided without evolving over time. These data suggest that cells responding to exoenzyme S would rapidly express proinflammatory cytokines and chemokines that may contribute to pulmonary inflammation in cystic fibrosis.

Epelman, Slava; Bruno, Tony F.; Neely, Graham G.; Woods, Donald E.; Mody, Christopher H.

2000-01-01

211

Transforming growth factor alpha (TGF-alpha) and other targets of tumor necrosis factor-alpha converting enzyme (TACE) in murine polycystic kidney disease.  

PubMed

Transforming growth factor-alpha (TGF-alpha) is abnormally expressed in autosomal recessive polycystic kidney disease (ARPKD). Tumor necrosis factor-alpha converting enzyme (TACE), a metalloproteinase, mediates TGF-alpha processing. In this study, we sought to determine whether TGF-alpha was an absolute requirement for renal cystogenesis and whether its absence would modulate disease severity or related growth factors/receptors expression. Bpk heterozygotes were bred with TGF-alpha null mice to produce cystic and noncystic offspring with or without TGF-alpha. Assessments included kidney weight (KW), body weight (BW), blood urea nitrogen (BUN), and kidney and liver immunohistology. Western analysis assessed kidney expression of amphiregulin (AR), epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), and their receptors, EGFR and ErbB4. A PCR-based methodology for genotyping bpk mice was also developed. No significant differences in KW, BW, KW/BW%, or BUN were seen in cystic mice with versus without TGF-alpha. Cystic kidney disease and liver disease histology were similar. AR, EGF, HB-EGF, EGFR, and ErbB4 were abnormally expressed to an equal degree in kidneys of mice with versus without TGF-alpha. Although previous data suggest a critical role of TGF-alpha in murine PKD, these data show that TGF-alpha is not required for renal cyst formation or kidney or liver disease progression. We speculate that the therapeutic effect of WTACE2 could have been due to effects on several TACE targets, including TGF-alpha, AR, and ErbB4, as well as metalloproteinases other than TACE. PMID:15774823

Nemo, Raghad; Murcia, Noel; Dell, Katherine Macrae

2005-03-17

212

Tumor necrosis factor alpha increases intestinal permeability in mice with fulminant hepatic failure  

PubMed Central

AIM: To determine the effect of tumor necrosis factor alpha (TNF-?) on intestinal permeability (IP) in mice with fulminant hepatic failure (FHF), and the expression of tight junction proteins. METHODS: We selected D-lactate as an index of IP, induced FHF using D-galactosamine/lipopolysaccharide and D-galactosamine/TNF-?, assessed the results using an enzymatic-spectrophotometric method, transmission electron microscopy, immunohistochemistry, Western blotting and real-time quantitative polymerase chain reaction. The effect of the administration of anti-TNF-? immunoglobulin G (IgG) antibody, before the administration of D-galactosamine/lipopolysaccharide, on TNF-? was also assessed. RESULTS: IP was significantly increased in the mouse model of FHF 6 h after injection (13.57 ± 1.70 mg/L, 13.02 ± 1.97 mg/L vs 3.76 ± 0.67 mg/L, P = 0.001). Electron microscopic analysis revealed tight junction (TJ) disruptions, epithelial cell swelling, and atrophy of intestinal villi. Expression of occludin and claudin-1 mRNA was significantly decreased in both FHF models (occludin: 0.57 ± 0.159 fold vs baseline, P = 0.000; claudin-1: 0.3067 ± 0.1291 fold vs baseline, P = 0.003), as were the distribution density of proteins in the intestinal mucosa and the levels of occludin and claudin-1 protein (occludin: 0.61 ± 0.0473 fold vs baseline, P = 0.000; claudin-1: 0.6633 ± 0.0328 fold vs baseline, P = 0.000). Prophylactic treatment with anti-TNF-? IgG antibody prevented changes in IP (4.50 ± 0.97 mg/L vs 3.76 ± 0.67 mg/L, P = 0.791), intestinal tissue ultrastructure, and the mRNA levels of occludin and claudin-1 expression (occludin: 0.8865 ± 0.0274 fold vs baseline, P = 0.505; claudin-1: 0.85 ± 0.1437 fold vs baseline, P = 0.1), and in the protein levels (occludin: 0.9467 ± 0.0285 fold vs baseline, P > 0.05; claudin-1: 0.9533 ± 0.0186 fold vs baseline, P = 0.148). CONCLUSION: Increased in IP stemmed from the downregulation of the TJ proteins occludin and claudin-1, and destruction of the TJ in the colon, which were induced by TNF-? in FHF mice.

Li, Guo-Zhen; Wang, Zhao-Han; Cui, Wei; Fu, Jin-Long; Wang, Yu-Rong; Liu, Pei

2012-01-01

213

Tumor necrosis factor-alpha induced enhancement of cryosurgery  

NASA Astrophysics Data System (ADS)

Local recurrence of cancer after cryosurgery is related to the inability to monitor and predict destruction of cancer (temperatures > -40°C) within an iceball. We previously reported that a cytokine adjuvant TNF-? could be used to achieve complete cancer destruction at the periphery of an iceball (0 to -40°C). This study is a further development of that work in which cryosurgery was performed using cryoprobes operating at temperatures > -40°C. LNCaP Pro 5 tumor grown in a dorsal skin fold chamber (DSFC) was frozen at -6°C after TNF-? incubation for 4 or 24 hours. Tumors grown in the hind limb were frozen with a probe tip temperature of -40°C, 4 or 24 hours after systemic injection with TNF-?. Both cryosurgery alone or TNF-? treatment alone caused only a minimal damage to the tumor tissue at the conditions used in the study. The combination of TNF-? and cryosurgery produced a significant damage to the tumor tissue in both the DSFC and the hind limb model system. This augmentation in cryoinjury was found to be time-dependent with 4-hour time period between the two treatments being more effective than 24-hour. These results suggests the possibility of cryotreatment at temperatures > -40°C with the administration of TNF-?.

Goel, Raghav; Paciotti, Guilio F.; Bischof, John C.

2008-03-01

214

Prior peritoneal lavage with hot 0.9 % saline induces HSP70 expression and protects against cerulein-induced acute pancreatitis in rats.  

PubMed

Recent studies have indicated that pre-induction of heat shock protein 70 (HSP70) expression in the pancreas protects against secretagogue-induced pancreatitis. In those studies, the HSP70 was mostly induced by unfeasible conditions. The aim of this current study was to investigate the effect of peritoneal lavage with hot 0.9 % saline (42 °C) on the pancreatic expression of HSP70 and its protective effect on cerulein-induced acute pancreatitis in rats. Male Wistar rats were peritoneally lavaged with 0.9 % saline at 42 °C for 30 min. HSP70 expression was evaluated by western blotting analysis. Prior peritoneal lavages with hot and warm saline were performed. Acute pancreatitis was induced by administration of intraperitoneal injection of cerulein (20 ?g/kg) four times, and its severity was assessed by measuring serum amylase, tumor necrosis factor-alpha (TNF-?), interleukin-6 (IL-6), and trypsinogen activation peptide (TAP) levels. Pancreatic sections were stained with hematoxylin and eosin for histological evaluation. Peritoneal lavage with hot 0.9 % saline increased intrapancreatic HSP70 expression and ameliorated the cerulein-induced pancreatitis in rats, judged by the significantly reduced serum amylase, TNF-?, and IL-6 concentrations; histopathological scores, and serum TAP levels. Peritoneal lavage with hot 0.9 % saline can induce HSP70 expression and prevent cerulein-induced acute pancreatitis in rats. The results suggest that HSP70 protects against cerulein-induced pancreatitis by preventing proinflammatory cytokine synthesis and trypsinogen activation during acute pancreatitis. PMID:23096089

Meng, Ke; Liu, Qingsen; Dou, Yan; Huang, Qiyang

2012-10-21

215

Tumor necrosis factor alpha inhibits olfactory regeneration in a transgenic model of chronic rhinosinusitis-associated olfactory loss  

PubMed Central

Background Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). Although olfactory sensory neurons (OSNs) are normally regenerated constantly in the olfactory epithelium (OE), a transgenic model of CRS-associated olfactory loss (inducible olfactory inflammation [IOI] mouse) shows that inflammation causes widespread OSN loss without progenitor cell proliferation. In this study, we further examine whether the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) inhibits olfactory regeneration. Methods IOI mice underwent either unilateral bulbectomy or sham surgery and then were induced to express TNF-alpha in the OE for 1 week. After death, the mice were assessed histologically and with bromodeoxyuridine staining to determine the effect of TNF-alpha on olfactory regeneration. Results In the absence of TNF-alpha, bulbectomy was associated with death of OSNs, followed by robust proliferation of neural progenitors and regrowth of the OE. At 12 days postbulbectomy, OE thickness on the operated side had recovered to >80% of the unoperated side. In mice in which TNF-alpha expression was induced, significantly reduced proliferation was observed, associated with failure of normal reconstitution of OE thickness. Conclusion The mechanism of olfactory dysfunction in CRS remains incompletely understood. Previous studies with a transgenic mouse model suggested that inflammation inhibits progenitor cell proliferation and olfactory regeneration. Here, the role of the CRS-associated cytokine TNF-alpha was investigated using surgical ablation of the olfactory bulb to stimulate synchronous OSN turnover. We find that TNF-alpha expression prevents normal OE recovery, supporting the role of suppressed olfactory regeneration in the pathophysiology of CRS-associated olfactory loss.

Turner, Justin H.; Liang, Kai Li; May, Lindsey; Lane, Andrew P.

2010-01-01

216

Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases  

PubMed Central

IL-32 is a newly described cytokine in the human found to be an in vitro inducer of tumor necrosis factor alpha (TNF?). We examined the in vivo relationship between IL-32 and TNF?, and the pathologic role of IL-32 in the TNF?-related diseases – arthritis and colitis. We demonstrated by quantitative PCR assay that IL-32 mRNA was expressed in the lymphoid tissues, and in stimulated peripheral T cells, monocytes, and B cells. Activated T cells were important for IL-32 mRNA expression in monocytes and B cells. Interestingly, TNF? reciprocally induced IL-32 mRNA expression in T cells, monocyte-derived dendritic cells, and synovial fibroblasts. Moreover, IL-32 mRNA expression was prominent in the synovial tissues of rheumatoid arthritis patients, especially in synovial-infiltrated lymphocytes by in situ hybridization. To examine the in vivo relationship of IL-32 and TNF?, we prepared an overexpression model mouse of human IL-32? (BM-hIL-32) by bone marrow transplantation. Splenocytes of BM-hIL-32 mice showed increased expression and secretion of TNF?, IL-1?, and IL-6 especially in response to lipopolysaccharide stimulation. Moreover, serum TNF? concentration showed a clear increase in BM-hIL-32 mice. Cell-sorting analysis of splenocytes showed that the expression of TNF? was increased in resting F4/80+ macrophages, and the expression of TNF?, IL-1? and IL-6 was increased in lipopolysaccharide-stimulated F4/80+ macrophages and CD11c+ dendritic cells. In fact, BM-hIL-32 mice showed exacerbation of collagen-antibody-induced arthritis and trinitrobenzen sulfonic acid-induced colitis. In addition, the transfer of hIL-32?-producing CD4+ T cells significantly exacerbated collagen-induced arthritis, and a TNF? blockade cancelled the exacerbating effects of hIL-32?. We therefore conclude that IL-32 is closely associated with TNF?, and contributes to the exacerbation of TNF?-related inflammatory arthritis and colitis.

Shoda, Hirofumi; Fujio, Keishi; Yamaguchi, Yumi; Okamoto, Akiko; Sawada, Tetsuji; Kochi, Yuta; Yamamoto, Kazuhiko

2006-01-01

217

The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model.  

PubMed

Sepsis is the leading cause of death for intensive care patients. Lipopolysaccharide (LPS) administration to animals under anesthesia is a strategy for the study of uncontrolled release of proinflammatory cytokines. Anesthetics have been indicated that they can specially affect immune responses, such as the inflammatory response. Pentobarbital is an anesthetic used mainly in animal studies. Thus, the effect of pentobarbital on tumor necrosis factor-alpha (TNF-alpha) release was determined. The results revealed that pentobarbital suppressed the expression of TNF-alpha mRNA and its proteins, which may result from the decrease in the activities of nuclear factor-kappaB and activator protein 1 and the reduction of the expression of p38 mitogen-activated protein kinase by pentobarbital. After the inhibitory activity of the pentobarbital for TNF-alpha release was proven in vivo, the cytotoxic effects of LPS were examined in vivo with or without pentobarbital treatments. In vivo results indicated that plasma levels of alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, serum urea nitrogen, and amylase decreased dramatically in the anesthetic group with pentobarbital administration. Finally, the effect of pentobarbital on TNF-alpha-related cell death was monitored in vitro, and the results indicated the pentobarbital could directly enhance the viabilities of cells under the treatment of TNF-alpha and protected cells from apoptosis induced by deferoxamine mesylate-induced hypoxia. These results suggest that pentobarbital significantly influences the LPS-induced inflammatory response and protects cells from death directly and indirectly induced by TNF-alpha. The information provides a perspective to re-evaluate the results of the experiments in which animals were anesthetized with pentobarbital. The anti-inflammatory effects of the drugs may have been caused by the synergistic effect of pentobarbital. PMID:17545946

Yang, Fwu Lin; Li, Chi Han; Hsu, Bang Gee; Tsai, Nu-Man; Lin, Shinn Zong; Harn, Horng Jyh; Chen, Hsing I; Liao, Kuang Wen; Lee, Ru Ping

2007-09-01

218

Tumor necrosis factor alpha in children with sickle cell disease in stable condition.  

PubMed Central

Tumor necrosis factor alpha (TNF-alpha) is known to induce wasting in humans and animals. This study was undertaken to determine TNF-alpha concentrations in children with sickle cell disease (SCD) and whether high TNF-alpha levels are more likely to be present in children with growth deficits, infection, or pain crisis. Tumor necrosis factor alpha was measured using enzyme immunoassay in 143 blood samples obtained from 101 children. Mean TNF-alpha levels were higher in patients (50 pg/mL) than in 21 control children (19 pg/mL) and in 26 laboratory employees (20 pg/mL). During the follow-up period, 35%, 38%, and 28% of children with SCD had infection, pain crisis, or a blood transfusion, respectively. Mean TNF-alpha concentrations were higher in children who had an infection than in those who did not. No significant effect of pain crisis or blood transfusion was observed. Tumor necrosis factor alpha concentrations were above normal (> 40 pg/mL) in 15% of controls, 34% of children with SCD, and 52% of children with SCD who had an infection and 33% of those who did not. A higher percentage of children who had elevated TNF-alpha levels had weight (46% versus 31%) or height (50% versus 28.6%) deficits than children who had normal TNF-alpha levels. These results indicate that most children with SCD in stable condition have normal TNF-alpha concentrations and that those with high TNF-alpha levels are more likely to have growth deficits.

Kuvibidila, S.; Gardner, R.; Ode, D.; Yu, L.; Lane, G.; Warrier, R. P.

1997-01-01

219

Effect of cellular differentiation on cytokine-induced expression of human immunodeficiency virus in chronically infected promonocytic cells: dissociation of cellular differentiation and viral expression.  

PubMed Central

Cellular differentiation is thought to play an important role in the susceptibility of monocytic lineage cells to human immunodeficiency virus (HIV) infection as well as in their ability to support virus replication. In addition, virus replication in monocytes/macrophages has been demonstrated in vitro to be strongly modulated by several cytokines such as tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor. The purpose of the present study was to investigate the interaction between cellular differentiation and cytokines in the regulation of HIV expression from chronically infected monocytic lineage cells. U1, a persistently HIV-infected promonocytic cell line, is characterized by low levels of virus expression which can be modulated by several cytokines. 1 alpha,-25-Dihydroxyvitamin D3 (Vit.D3), a well-known differentiating agent for myelomonocytic cells which has been previously reported to modulate HIV replication in other in vitro systems, induced maturation of U1 cells toward a macrophage-like phenotype, as demonstrated by the induction of the differentiation-associated cell surface markers CD14 and CD11b. Vit.D3-induced differentiation did not result in induction of HIV expression; however, when U1 cells were stimulated with tumor necrosis factor alpha in the presence of Vit.D3, a synergistic induction of cell differentiation and viral expression was demonstrated. In contrast, Vit.D3 suppressed the induction of HIV expression in U1 cells stimulated with gamma interferon, interleukin-6, and granulocyte-macrophage colony-stimulating factor, although synergy between Vit.D3 and these cytokines was observed in terms of cellular differentiation. These data suggest that differentiation of monocytic cells does not necessarily correlate with increased HIV expression.

Goletti, D; Kinter, A L; Biswas, P; Bende, S M; Poli, G; Fauci, A S

1995-01-01

220

Autocrine Stimulation of Interleukin-1(alpha) and Transforming Growth Factor(alpha) Production in Human Keratinocytes and Its Antagonism by Glucocorticoids.  

National Technical Information Service (NTIS)

Interleukin-1 (IL-1) and transforming growth factor alpha (TGF alpha) mRNA expression were analyzed in cultured normal human keratinocytes. Keratinocytes express IL-1 mRNA when cultured in keratinocyte growth medium but not in Dulbecco's minimal essential...

S. W. Lee V. B. Morhenn M. Ilnicka E. M. Eugui A. C. Allison

1989-01-01

221

The development of novel inhibitors of tumor necrosis factor-alpha production based on substituted [5,5]-bicyclic pyrozolones  

SciTech Connect

Novel substituted [5,5]-bicyclic pyrzazolones are presented as inhibitors of tumor necrosis factor-{alpha} (TNF-{alpha}) production. Many of these compounds show low nanomolar activity against lipopolysaccaride (LPS)-induced TNF-{alpha} production in THP-1 cells. This class of molecules was co-crystallized with mutated p38, and several analogs showed good oral bioavailability in the rat. Oral activity of these compounds in the rat iodoacetate model for osteoarthritis is discussed.

Laufersweiler, Matthew; Brugel, Todd; Clark, Michael; Golebiowski, Adam; Bookland, Roger; Laughlin, Steven; Sabat, Mark; Townes, Jennifer; VanRens, John; De, Biswanath; Hsieh, Lily; Heitmeyer, Sandra; Juergens, Karen; Brown, Kimberly; Mekel, Marlene; Walter, Richard; Janusz, Michael (PG)

2010-11-16

222

Pseudomonas aeruginosa Exoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines  

Microsoft Academic Search

Pseudomonas aeruginosa infection of cystic fibrosis patients causes lung damage that is substantially orches- trated by cytokines. In this study, multi-gene probe analysis was used to characterize the ability of the P. aeru- ginosa mitogen, exoenzyme S, to induce proinflammatory and immunoregulatory cytokines and chemokines. Exoenzyme S strongly induced transcription of proinflammatory cytokines and chemokines (tumor necrosis factor alpha, interleukin-1a

SLAVA EPELMAN; TONY F. BRUNO; GRAHAM G. NEELY; DONALD E. WOODS; C. H. Mody

2000-01-01

223

Role of tumor necrosis factor alpha in activation and replication of the tat-defective human immunodeficiency virus type 1.  

PubMed Central

Transcription of human immunodeficiency virus type 1 (HIV-1) depends on the function of the virus-encoded regulatory protein Tat, which interacts with the specific Tat response (TAR) element present in the leader sequence of all HIV-1 RNAs. In this study, we examined whether tumor necrosis factor alpha (TNF-alpha) can replace the requirement for a functional Tat protein. We found that TNF-alpha can induce expression of a latent, tat-defective virus and support its replication both in T cells and in primary mononuclear cells. Analysis of the transcriptional rate of the tat-defective HIV-1 transcriptional unit indicates that TNF-alpha stimulates the initiation of transcription but, in contrast to Tat protein, does not significantly reduce transcriptional polarity. Interestingly, we found that the processing of viral precursor proteins is altered in the absence of Tat. We propose that TNF-alpha-mediated induction of HIV-1 plays an essential role in the early stages of the virus life cycle and in viral latency. Images

Popik, W; Pitha, P M

1993-01-01

224

Collagenase-3 (matrix metalloproteinase-13) expression is induced in oral mucosal epithelium during chronic inflammation.  

PubMed Central

Increased proliferation of mucosal epithelium during inflammation is associated with degradation of subepithelial connective tissue matrix and local invasion of the epithelial cells. Here we have studied, whether collagenase-3 (MMP-13), a collagenolytic matrix metalloproteinase with an exceptionally wide substrate specificity, is expressed in the epithelium of chronically inflamed mucosa. Examination of human gingival tissue sections from subjects with chronic adult periodontitis with in situ hybridization revealed marked expression of MMP-13 in basal cells of some epithelial rete ridges expanding into connective tissue. Immunohistochemical staining demonstrated that these cells also expressed strongly laminin-5, suggesting that they are actively migrating cells. A strong signal for MMP-13 mRNA was occasionally also noted in the suprabasal epithelial cells facing the gingival pocket, whereas no collagenase-1 (MMP-1) mRNA was detected in any areas of the epithelium. MMP-13 expression was also detected in fibroblast-like cells associated with collagen fibers of the inflamed subepithelial connective tissue. In organ culture of human oral mucosa, MMP-13 mRNA expression was observed in epithelial cells growing into connective tissue of the specimens. Regulation of MMP-13 expression was examined in cultured normal nonkeratinizing epithelial cells isolated from porcine periodontal ligament. In these cells, MMP-13 expression at the mRNA and protein level was potently enhanced (up to sixfold) by tumor necrosis factor-alpha, transforming growth factor-beta(1), and transforming growth factor-alpha and by keratinocyte growth factor in the presence of heparin. In addition, plating periodontal ligament epithelial cells on type I collagen stimulated MMP-13 expression (sevenfold) as compared with cells grown on tissue culture plastic. The results of this study show, that expression of MMP-13 is specifically induced in undifferentiated epithelial cells during chronic inflammation due to exposure to cytokines and collagen. Thus, it is likely that MMP-13 expression is instrumental in the subepithelial collagenolysis and local invasion of the activated mucosal epithelium into the connective tissue. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Uitto, V. J.; Airola, K.; Vaalamo, M.; Johansson, N.; Putnins, E. E.; Firth, J. D.; Salonen, J.; Lopez-Otin, C.; Saarialho-Kere, U.; Kahari, V. M.

1998-01-01

225

Downregulation of protein disulfide isomerase in sepsis and its role in tumor necrosis factor-alpha release  

PubMed Central

Introduction Protein disulfide isomerase (PDI) is an important factor for the protein modification step in the post-translational event. PDI plays an essential role in cell survival under various stress conditions. It has been reported that PDI can serve as a negative regulator of nuclear factor-kappa-B (NF-?B) and that it can inhibit lipopolysaccharide (LPS)-induced proinflammatory cytokine production in macrophages. Thus, PDI may be an intracellular anti-inflammatory molecule. Although we have previously shown that Kupffer cell-derived proinflammatory cytokines cause liver injury in sepsis, the effect of sepsis on PDI expression as well as the effect of PDI inhibition on cytokine production have not been investigated. We therefore hypothesized that sepsis downregulates PDI expression and that the inhibition of PDI promotes proinflammatory cytokine production. Method Adult male rats were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia (continuous infusion of 1 ?g/kg body weight LPS by an osmotic pump) for 20 hours. Hepatic tissues were collected and PDI gene expression was determined. In additional experiments, cells from a macrophage-like cell line, RAW 264.7, were treated with 100 ng/mL LPS for 4 hours and protein expressions were measured. RAW 264.7 cells were also treated with bacitracin, a specific PDI inhibitor, for 24 hours, and tumor necrosis factor-alpha (TNF-?) gene and protein expression as well as its release in the cell supernatant were determined. To further confirm the beneficial effect of PDI in sepsis, RAW 264.7 cells were transfected with PDI short interfering RNA (siRNA) and PDI gene expression and TNF-? release were measured by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Results PDI gene expression was significantly decreased by 28% and 69% at 20 hours after CLP or LPS infusion, respectively. LPS also decreased PDI protein expression by 33% in RAW 264.7 cells. Incubation of RAW 264.7 cells with bacitracin significantly increased TNF-? gene expression and TNF-? release as well as its cellular levels in a dose-dependent manner. Transfection of RAW 264.7 cells with PDI siRNA produced an average 36.8% inhibition of the PDI gene expression. This downregulation was correlated with a 3.19-fold increase in TNF-? release into the cell supernatant. Conclusion Taken together, these results suggest that downregulation of PDI by sepsis significantly increases proinflammatory cytokine production. Thus, prevention of PDI downregulation in sepsis may be a novel approach to attenuate hyperinflammation and to reduce tissue injury under such conditions.

Zhou, Mian; Jacob, Asha; Ho, Natalie; Miksa, Michael; Wu, Rongqian; Maitra, Subir R; Wang, Ping

2008-01-01

226

Protective role of ascorbic acid isolated from Cissus quadrangularis on NSAID induced toxicity through immunomodulating response and growth factors expression.  

PubMed

The present study investigate the effect of ascorbic acid, the major bioactive component isolated from Cissus quadrangularis extract (CAA) on inflammatory cytokines and growth factors in non-steroidal anti-inflammatory drug (NSAID) induced gastric ulcer. Analysis of serum cytokine profile using enzymelinked immunosorbent assay (ELISA) showed a drastic increase in interleukin (IL)-1beta, IL-6, tumour necrosis factor-alpha (TNF)-alpha, interferon-gamma (IFN-gamma) and decrease in IL-10, Il-4 and prostaglandin E2 (PGE2) levels in NSAID (aspirin) treated rats. The reduction of growth factors such as transforming growth factor-alpha (TGF)-alpha and vascular endothelial cell growth factor (VEGF) by aspirin was determined by immunohistochemistry method. Administration of CAA produced significant protection against aspirin induced gastric toxicity by showing significant increase in PGE2, TGF-alpha, VEGF expression and accompanied by a significant inhibition of nitric oxide and regulating the levels of cytokines in rats. These findings suggest that CAA prevents gastric ulcer formation due to its immunomodulatory effect, antioxidant activity along with the ability to modulate PG synthesis and up-regulation of the growth factors. PMID:18773975

Jainu, Mallika; Mohan, Kunju Vijai

2008-09-04

227

Cellular and molecular evidence for a role of tumor necrosis factor alpha in the ovulatory mechanism of trout  

PubMed Central

Background The relevance of immune-endocrine interactions to the regulation of ovarian function in teleosts is virtually unexplored. As part of the innate immune response during infection, a number of cytokines such as tumor necrosis factor alpha (TNF alpha) and other immune factors, are produced and act on the reproductive system. However, TNF alpha is also an important physiological player in the ovulatory process in mammals. In the present study, we have examined for the first time the effects of TNF alpha in vitro in preovulatory ovarian follicles of a teleost fish, the brown trout (Salmo trutta). Methods To determine the in vivo regulation of TNF alpha expression in the ovary, preovulatory brook trout (Salvelinus fontinalis) were injected intraperitoneally with either saline or bacterial lipopolysaccharide (LPS). In control and recombinant trout TNF alpha (rtTNF alpha)-treated brown trout granulosa cells, we examined the percentage of apoptosis by flow cytometry analysis and cell viability by propidium iodide (PI) staining. Furthermore, we determined the in vitro effects of rtTNF alpha on follicle contraction and testosterone production in preovulatory brown trout ovarian follicles. In addition, we analyzed the gene expression profiles of control and rtTNF alpha-treated ovarian tissue by microarray and real-time PCR (qPCR) analyses. Results LPS administration in vivo causes a significant induction of the ovarian expression of TNF alpha. Treatment with rtTNF alpha induces granulosa cell apoptosis, decreases granulosa cell viability and stimulates the expression of genes known to be involved in the normal ovulatory process in trout. In addition, rtTNF alpha causes a significant increase in follicle contraction and testosterone production. Also, using a salmonid-specific microarray platform (SFA2.0 immunochip) we observed that rtTNF alpha induces the expression of genes known to be involved in inflammation, proteolysis and tissue remodeling. Furthermore, the expression of kallikrein, TOP-2, serine protease 23 and ADAM 22, genes that have been postulated to be involved in proteolytic and tissue remodeling processes during ovulation in trout, increases in follicles incubated in the presence of rtTNF alpha. Conclusions In view of these results, we propose that TNF alpha could have an important role in the biomechanics of follicle weakening, ovarian rupture and oocyte expulsion during ovulation in trout, primarily through its stimulation of follicular cell apoptosis and the expression of genes involved in follicle wall proteolysis and contraction.

2010-01-01

228

Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.  

PubMed

Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy. PMID:20486929

Bahia, Malkeet S; Silakari, Om

2010-05-01

229

Hyper-inducible expression system for streptomycetes  

PubMed Central

Streptomycetes produce useful enzymes and a wide variety of secondary metabolites with potent biological activities (e.g., antibiotics, immunosuppressors, pesticides, etc.). Despite their importance in the pharmaceutical and agrochemical fields, there have been no reports for practical expression systems in streptomycetes. Here, we developed a “PnitA-NitR” system for regulatory gene expression in streptomycetes based on the expression mechanism of Rhodococcus rhodochrous J1 nitrilase, which is highly induced by an inexpensive and safe inducer, ?-caprolactam. Heterologous protein expression experiments demonstrated that the system allowed suppressed basal expression and hyper-inducible expression, yielding target protein levels of as high as ?40% of all soluble protein. Furthermore, the system functioned in important streptomycete strains. Thus, the PnitA-NitR system should be a powerful tool for improving the productivity of various useful products in streptomycetes.

Herai, Sachio; Hashimoto, Yoshiteru; Higashibata, Hiroki; Maseda, Hideaki; Ikeda, Haruo; Omura, Satoshi; Kobayashi, Michihiko

2004-01-01

230

Hyper-inducible expression system for streptomycetes.  

PubMed

Streptomycetes produce useful enzymes and a wide variety of secondary metabolites with potent biological activities (e.g., antibiotics, immunosuppressors, pesticides, etc.). Despite their importance in the pharmaceutical and agrochemical fields, there have been no reports for practical expression systems in streptomycetes. Here, we developed a "P(nitA)-NitR" system for regulatory gene expression in streptomycetes based on the expression mechanism of Rhodococcus rhodochrous J1 nitrilase, which is highly induced by an inexpensive and safe inducer, epsilon-caprolactam. Heterologous protein expression experiments demonstrated that the system allowed suppressed basal expression and hyper-inducible expression, yielding target protein levels of as high as approximately 40% of all soluble protein. Furthermore, the system functioned in important streptomycete strains. Thus, the P(nitA)-NitR system should be a powerful tool for improving the productivity of various useful products in streptomycetes. PMID:15377796

Herai, Sachio; Hashimoto, Yoshiteru; Higashibata, Hiroki; Maseda, Hideaki; Ikeda, Haruo; Omura, Satoshi; Kobayashi, Michihiko

2004-09-17

231

A Tumor Necrosis Factor-Alpha-Mediated Pathway Promoting Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous mutations in either PKD1 or PKD2, genes that encode polycystin (PC) -1 and -2, respectively 1. We show here that tumor necrosis factor-alpha (TNF-?), an inflammatory cytokine present in human ADPKD cystic fluid, disrupts the localization of PC2 to the plasma membrane and primary cilia through a scaffold protein, FIP2, which is induced by TNF-?. Treatment of mouse embryonic kidney organ cultures with TNF-? resulted in formation of cysts, and this effect was exacerbated in the Pkd2+/? kidneys. TNF-? also stimulated cyst formation in vivo in Pkd2+/? mice. In contrast, treatment of Pkd2+/? mice with the TNF-? inhibitor, etanercept, prevented cyst formation. These data reveal a pathway connecting TNF-? signaling, polycystins and cystogenesis, the activation of which may reduce functional PC2 below a critical threshold, precipitating the ADPKD cellular phenotype.

Li, Xiaogang; Magenheimer, Brenda S.; Xia, Sheng; Johnson, Teri; Wallace, Darren P.; Calvet, James P.; Li, Rong

2012-01-01

232

Increased hypoxia-inducible factor 1? expression in lung cells of horses with recurrent airway obstruction  

PubMed Central

Background Recurrent airway obstruction (RAO, also known as equine heaves) is an inflammatory condition caused by exposure of susceptible horses to organic dusts in hay. The immunological processes responsible for the development and the persistence of airway inflammation are still largely unknown. Hypoxia-inducible factor (Hif) is mainly known as a major regulator of energy homeostasis and cellular adaptation to hypoxia. More recently however, Hif also emerged as an essential regulator of innate immune responses. Here, we aimed at investigating the potential involvement of Hif1-? in myeloid cells in horse with recurrent airway obstruction. Results In vitro, we observed that Hif is expressed in equine myeloid cells after hay dust stimulation and regulates genes such as tumor necrosis factor alpha (TNF-?), interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGF-A). We further showed in vivo that airway challenge with hay dust upregulated Hif1-? mRNA expression in myeloid cells from the bronchoalveolar lavage fluid (BALF) of healthy and RAO-affected horses, with a more pronounced effect in cells from RAO-affected horses. Finally, Hif1-? mRNA expression in BALF cells from challenged horses correlated positively with lung dysfunction. Conclusion Taken together, our results suggest an important role for Hif1-? in myeloid cells during hay dust-induced inflammation in horses with RAO. We therefore propose that future research aiming at functional inactivation of Hif1 in lung myeloid cells could open new therapeutic perspectives for RAO.

2012-01-01

233

Role of MyD88 in Diminished Tumor Necrosis Factor Alpha Production by Newborn Mononuclear Cells in Response to Lipopolysaccharide  

Microsoft Academic Search

Human newborns are more susceptible than adults to infection by gram-negative bacteria. We hypothesized that this susceptibility may be associated with a decreased response by leukocytes to lipopolysaccharide (LPS). In this study, we compared LPS-induced secretion of tumor necrosis factor alpha (TNF-) by mononuclear cells (MNC) from adult peripheral blood and newborn umbilical cord blood in vitro and attempted to

Sen Rong Yan; Gefei Qing; David M. Byers; Andrew W. Stadnyk; Walla Al-Hertani; Robert Bortolussi

2004-01-01

234

Metabolic and lactational responses during recombinant bovine tumor necrosis factor-alpha treatment in lactating cows.  

PubMed

This study examined the effects of recombinant bovine tumor necrosis factor-alpha (rbTNF) administration on metabolic and hormonal responses and lactational performance in dairy cows. Twelve lactating Holstein cows were injected subcutaneously with rbTNF (2.5 microg per kg per d) or saline (3 ml per head per d) at 1200 h daily for 7 d (d 0-6) and used in a crossover design. The rbTNF treatment induced increases in plasma haptoglobin, nonesterified fatty acid, cortisol, and growth hormone levels compared with the control levels. The rbTNF-treated cows had lower triiodothyronine and insulin-like growth factor-1 concentrations than control cows. In a somatoliberin challenge on d 6, the somatotropin response to somatoliberin (0.25 microg/kg) was smaller in the rbTNF group than in the control. The rbTNF treatment also produced increases of the nitrite plus nitrate concentration in plasma and milk during the period between d 1 and 7. Milk yield was reduced by rbTNF administration from d 1 to 8. The percentage of milk fat was increased on d 1-7 by rbTNF treatment, but milk protein content in the rbTNF group was decreased on d 5 and 7 as compared with that in the control group. These results support the possibility that tumor necrosis factor-alpha is responsible for the changes in hormone secretion, milk production and composition, and inflammatory parameters observed during coliform mastitis. PMID:12703618

Kushibiki, S; Hodate, K; Shingu, H; Obara, Y; Touno, E; Shinoda, M; Yokomizo, Y

2003-03-01

235

Metabolic effects of tumour necrosis factor alpha in NMRI mice.  

PubMed Central

Following a single injection of 7.5 x 10(7) U kg-1 of human recombinant tumour necrosis factor-alpha (TNF-alpha) to female NMRI mice, marked hypoglycaemia was observed within a 2 h period, accompanied by a severe depletion of liver glycogen and a drop in rectal body temperature when compared with pair-fed controls. There was no alteration in plasma alanine, lactate or pyruvate values, but an elevation of acetoacetate and 3-hydroxybutyrate when compared with pair-fed controls. Production of 14CO2 from U-14C-glucose was reduced in TNF-alpha treated animals, while production of 14CO2 from U-14C-palmitate was not significantly different from controls, suggesting that the glucose was not being used to provide an increased metabolic rate. Glucose utilisation by different tissues was investigated by the 2-deoxyglucose tracer method. This showed that 2 h following TNF-alpha infusion glucose utilisation was increased in colon, liver, kidney and spleen by 500, 350, 36 and 25% respectively. However, when calculated on a whole-animal basis the major contributor to the increased glucose consumption was the liver. Plasma levels of both FFA and triglycerides were also elevated in TNF-alpha treated animals, suggesting that increased consumption of glucose by the liver may be utilised for lipogenesis. The rate of conversion of glucose into lipids in the liver was more than doubled 2 h after TNF-alpha administration with a concomitant rise in plasma and adipose tissue. These results suggest that administration of TNF-alpha produces a severe hypoglycaemia in order to serve an increased lipogenesis in liver and adipose tissue, which appears to be independent of the anorectic effect.

Mahony, S. M.; Tisdale, M. J.

1990-01-01

236

Differential cytokine expression in skin graft healing in inducible nitric oxide synthase knockout mice.  

PubMed

Inducible nitric oxide synthase (iNOS) and its product, nitric oxide, have been shown to play important roles in wound biology. The present study was performed to investigate the role of iNOS in modulating the cytokine cascade during the complex process of skin graft wound healing.Fifteen iNOS-knockout mice and 15 wild-type C57BL/6J mice were subjected to autogenous 1-cm2 intrascapular full-thickness skin grafts. Three animals in each group were killed on postoperative days 3, 5, 7, 10, and 14. Specimens were then analyzed using nonisotopic in situ hybridization versus mRNA of tumor growth factor-beta1, vascular endothelial growth factor, iNOS, endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha, and basic fibroblast growth factor, as well as positive and negative control probes. Positive cells in both grafts and wound beds were counted using a Leica microgrid. Scar thickness was measured with a Leica micrometer. Data were analyzed using the unpaired Student's t test. Expression of iNOS was 2- to 4-fold higher in knockout mice than in wild-type mice on postoperative days 5, 7, and 14. Expression of eNOS was 2- to 2.5-fold higher in knockout mice than in wild-type mice on postoperative days 5 and 7. Tumor necrosis factor-alpha expression was 2- to 7-fold higher in knockout mice than in wild-type mice on all postoperative days. In contrast, expression levels of angiogenic/fibrogenic cytokines (vascular endothelial growth factor, basis fibroblast growth factor, and tumor growth factor-beta1) were 2.5- to 4-fold higher in wild-type mice than in knockout mice. Scars were 1.5- to 2.5-fold thicker in knockout mice than in wild-type mice at all time points. All of the above results represent statistically significant differences (p < 0.05). Significantly different patterns of cytokine expression were seen in knockout and wild-type mice. Although the scar layer was thicker in knockout mice, it showed much greater infiltration with inflammatory cells. These data further delineate the modulatory effect of iNOS and nitric oxide in healing skin grafts. PMID:11604628

Most, D; Efron, D T; Shi, H P; Tantry, U S; Barbul, A

2001-10-01

237

Dilinoleoylphosphatidylcholine induces the expression of the anti-inflammatory heme oxygenase-1 in RAW264.7 macrophages.  

PubMed

1,2-Dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), the main and active component of soybean lecithin, has been reported to exert anti-inflammatory effects, but the underlying mechanisms remain to be established. It was found that DLPC could induce the expression of the anti-inflammatory heme oxygenase-1 (HO-1) through the activation of nuclear erythroid 2-related factor 2 (Nrf2) in RAW264.7 macrophages. Pretreatment with DLPC suppressed the expression of inducible nitric oxide (NO) synthase (iNOS), one of proinflammatory enzymes, and reduced NO production in lipopolysaccharide (LPS)-stimulated macrophages. Similarly, DLPC also diminished the production of tumor necrosis factor-alpha (TNF-alpha), one of proinflammatory cytokines. Interestingly, the inhibitory effects of DLPC on LPS-induced iNOS expression and TNF-alpha production were reversed by tin protoporphyrin, a HO-1 inhibitor. Thus, HO-1 expression via Nrf2 activation may be one of the possible mechanisms explaining the anti-inflammatory effects of DLPC. PMID:20336709

Son, Yong; Lee, Ju Hwan; Kim, Nam-Ho; Surh, Na-Young; Kim, Eun-Cheol; Chung, Hun-Taeg; Kang, Dae Gill; Pae, Hyun-Ock

238

Modulation of cytokine-induced HIV gene expression by competitive binding of transcription factors to the coactivator p300.  

PubMed Central

The host response to viral infection involves the secretion of multiple cytokines which alter immune function and viral replication. These proteins activate several signal transduction pathways in infected cells which must be integrated to regulate cellular and viral gene expression. In this report, we demonstrate that specific transcription factors induced by distinct cytokines regulate HIV transcription by competitive binding to the p300 coactivator. Interferon-alpha (IFN-alpha) was found to inhibit NF-kappaB-dependent HIV gene expression stimulated by tumor necrosis factor-alpha (TNF-alpha). This inhibition was mediated by binding of the IFN-alpha signal transducer and activator of transcription 2, Stat2, to a specific domain of p300 which also binds to the RelA (p65) subunit of NF-kappaB. p300 was found to be limiting with respect to RelA (p65) and Stat2, and this effect was reversed by overexpression of p300. Inhibition by Stat2 was specific for NF-kappaB and was not mediated by Stat1, which is also induced by IFN-alpha. Gene activation induced by the Stat2 transcription domain was also inhibited by expression of RelA. These results demonstrate that HIV transcription can be regulated in the nucleus by competitive binding of specific cytokine-induced transcription factors to a discrete domain of a transcriptional coactivator.

Hottiger, M O; Felzien, L K; Nabel, G J

1998-01-01

239

Tumour necrosis factor alpha mediated apoptosis in murine macrophages by Salmonella enterica serovar Typhi under oxidative stress.  

PubMed

Invasive Salmonella has been reported to induce apoptosis of macrophages as part of its infection process, which may allow it to avoid detection by the innate immune system. However, the induction of apoptosis under the different host environments remains to be examined, including the oxidative stress experienced by pathogens in the macrophage milieu. To simulate in vivo oxidative conditions, Salmonella enterica serovar Typhi was grown in the presence of hydrogen peroxide and its ability to induce apoptosis of murine macrophages was assessed. Analysis of data revealed that oxidative stressed S. Typhi caused apoptotic cell death in 51% of macrophages, whereas S. Typhi grown under normal conditions accounted for apoptotic cell death in only 32% of macrophages. A significant increase in the levels of oxidants and decrease in the antioxidant was also observed which correlated with the increased generation of tumour necrosis factor alpha, interleukin-1alpha and interleukin-6. These results suggest that tumour necrosis factor alpha in conjunction with other cytokines may induce apoptotic cell death through the up-regulation of lipid peroxidation and down-regulation of superoxide dismutase. This finding may help us to understand better the host-pathogen interactions and may be of clinical importance in the development of preventive intervention against infection. PMID:16831216

Chanana, Vishal; Majumdar, Siddharth; Rishi, Praveen

2006-07-01

240

Glial Tumor Necrosis Factor Alpha (TNF?) Generates Metaplastic Inhibition of Spinal Learning  

PubMed Central

Injury-induced overexpression of tumor necrosis factor alpha (TNF?) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNF? might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNF?. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNF? to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNF? and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNF? in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNF? activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNF? modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury.

Huie, J. Russell; Baumbauer, Kyle M.; Lee, Kuan H.; Bresnahan, Jacqueline C.; Beattie, Michael S.; Ferguson, Adam R.; Grau, James W.

2012-01-01

241

Endogenously produced nitric oxide increases tumor necrosis factor-alpha production in transfected human U937 cells.  

PubMed

Various functions of human phagocytes are modulated by nitric oxide (NO). We transfected the human U937 monoblastoid cell line with an expression vector containing human endothelial NO synthase (eNOS) or murine inducible NOS (iNOS) cDNA to study the regulatory role of NO without the nonspecific effects associated with exogenous NO sources. Western blot confirmed expression of eNOS or iNOS in respectively transfected cells, but not in naive or empty-vector transfected cells. Transfectants expressing iNOS, a calcium-independent enzyme, but not eNOS, a calcium-dependent enzyme, spontaneously produced NO (P < .001). The NO release from iNOS-transfected cells, as measured by nitrite and nitrate accumulation and by cyclic guanosine monophosphate (cGMP) increases in rat reporter cells, was inhibitable (P < .01 for both) with N(omega)-methyl-L-arginine (L-NMA), a NOS inhibitor. The eNOS transfectants were shown to contain functional enzyme by the conversion of L-arginine to L-citrulline in fractionated cells (P = .0001) and by exposing intact cells to calcium ionophore using the cGMP reporter cell assay (P = .0001). After differentiation with phorbol-12-myristate-13-acetate (PMA), iNOS transfectants produced more tumor necrosis factor-alpha (TNF-alpha) (124.9 +/- 25.4 pg/5 x 10(5) cells per 24 hours) than did empty-vector transfected cells (21.9 +/- 1.9 pg/5 x 10(5) cells per 24 hours; P = .02). This effect was inhibited by 500 micromol/L L-NMA (54.4 +/- 3.1 pg/5 x 10(5) cells per 24 hours; P = .05). However, in the presence of high concentrations of lipopolysaccharide (1 microg/mL), which further increased NO production in iNOS transfected cells (P = .044), TNF-alpha production was similar comparing PMA-differentiated iNOS and empty-vector transfectants (12.2 +/- 0.8 and 13.1 +/- 1.7 ng/5 x 10(5) cells per 24 hours, respectively; P = .5). The results show that under certain conditions endogenously produced NO can upregulate TNF-alpha production in human phagocytes. PMID:9242548

Yan, L; Wang, S; Rafferty, S P; Wesley, R A; Danner, R L

1997-08-01

242

Langerhans cells require signals from both tumour necrosis factor-alpha and interleukin-1 beta for migration.  

PubMed Central

The induction phase of contact sensitization is associated with the movement of epidermal Langerhans cells (LC) from the skin and their migration, via afferent lymphatics, to draining lymph nodes where they accumulate as immunostimulatory dendritic cells (DC). It has been demonstrated previously that tumour necrosis factor-alpha (TNF-alpha) provides an important signal for LC migration and that in the absence of this cytokine, movement of LC from the epidermis to regional lymph nodes is inhibited. Recent evidence indicates that interleukin-1 beta (IL-1 beta), a cytokine produced in murine epidermis exclusively by LC, may also play a role in LC migration. The purpose of the investigations described here was to clarify, using relevant neutralizing anti-cytokine antibodies, the contributions made by TNF-alpha and IL-1 beta to the migration of LC from the epidermis. It was found that like anti-TNF-alpha, anti-IL-1 beta administered systemically to mice (by intraperitoneal injection), prior to skin sensitization with the contact allergen oxazolone, resulted in a marked inhibition of DC accumulation in draining lymph nodes. It was shown also that anti-IL-1 beta inhibited TNF-alpha-induced LC migration and DC accumulation and that; in similar fashion, the stimulation of LC migration and DC accumulation induced by IL-1 beta was compromised by prior treatment with anti-TNF-alpha. Based upon these data it is proposed that the stimulation of LC migration in response to skin sensitization requires the receipt by LC of two independent signals, one provided by TNF-alpha and the other by IL-1 beta. Morphological analyses of LC in epidermal sheets prepared from animals exposed to these cytokines with or without prior systemic treatment with anti-cytokine antibody suggested that the changes induced in LC by TNF-alpha and IL-1 beta may include the altered expression of adhesion molecules and acquisition of the ability to interact with and pass through the basement membrane. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Cumberbatch, M; Dearman, R J; Kimber, I

1997-01-01

243

Inhibition of tumor necrosis factor-alpha by thalidomide in magnesium deficiency  

Microsoft Academic Search

The effect of thalidomide on circulating cytokines and myocardial lesion formation was investigated in Mg-deficient rats. After two weeks on a Mg-deficient diet, rats show an increase in circulating levels of tumor necrosis factor-alpha and interleukin 1. Thalidomide (1 mg\\/day) caused a complete inhibition of the increase in circulating tumor necrosis factor-alpha levels, without having an effect on interleukin 1.

William B. Weglicki; Richard E. Stafford; Benjamin F. Dickens; I. Tong Mak; Marie M. Cassidy; Terry M. Phillips

1993-01-01

244

Hypoxia induces apelin expression in human adipocytes  

PubMed Central

Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. To create a hypoxic tissue culture environment (defined as 1% O2, 94% N2 and 5% CO2) we used a modular incubator chamber. In addition, we mimicked hypoxic conditions by using CoCl2. The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1?. In our study we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1?.

Geiger, K.; Muendlein, A.; Stark, N.; Saely, C. H.; Wabitsch, M.; Fraunberger, P.; Drexel, H.

2011-01-01

245

Autocrine regulation of steroidogenic function of Leydig cells by transforming growth factor-alpha.  

PubMed

We have determined the effects of LH on the expression of transforming growth factor-alpha (TGFalpha) and epidermal growth factor receptor (EGFR) system in rat Leydig cells and investigated its role in steroidogenesis. LH and TGFalpha/epidermal growth factor (EGF) significantly increased the levels of TGFalpha mRNA and protein, and the levels of EGFR protein in immature rat Leydig cells (ILC). Treatment with TGFalpha or EGF for 24h resulted in significant increase in androgen production in ILC. The increase in androgen production in response to TGFalpha was associated with increased mRNA levels of SR-BI, steroidogenic acute regulatory (StAR) and P450scc but not of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and P450c17. TGFalpha also caused a marked increase in the levels StAR protein in ILC. EGFR inhibitor (AG1478) blocked the effects of TGFalpha while MEK-inhibitor (PD98059) potentiated TGFalpha or LH effects on steroidogenesis. A PKA inhibitor (H89) blocked both TGFalpha and LH effects on steroidogenesis. We conclude that TGFalpha plays an autocrine role in LH dependent development and function of Leydig cells. PMID:15353178

Millena, Ana Cecilia; Reddy, Sheila C; Bowling, Gretchen H; Khan, Shafiq A

2004-09-30

246

Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss.  

PubMed

Exogenous tumor necrosis factor-alpha (TNF-?) plays a role in auditory hair cell death by altering the expression of apoptosis-related genes in response to noxious stimuli. Little is known, however, about the function of TNF-? in normal hair cell physiology. We, therefore, investigated the cochlear morphology and auditory function of TNF-?-deficient mice. Auditory evoked brainstem response showed significantly higher thresholds, especially at higher frequencies, in 1-month-old TNF-?(-/-) mice as compared to TNF-?(+/-) and wild type (WT); hearing loss did not progress further from 1 to 4 months of age. There was no difference in the gross morphology of the organ of Corti, lateral wall, and spiral ganglion cells in TNF-?(-/-) mice compared to WT mice at 4 months of age, nor were there differences in the anatomy of the auditory ossicles. Outer hair cells were completely intact in surface preparations of the organ of Corti of TNF-?(-/-) mice, and synaptic ribbon counts of TNF-?(-/-) and WT mice at 4 months of age were similar. Reduced amplitudes of distortion product otoacoustic emissions, however, indicated dysfunction of outer hair cells in TNF-?(-/-) mice. Scanning electron microscopy revealed that stereocilia were sporadically absent in the basal turn and distorted in the middle turn. In summary, our results demonstrate that TNF-?-mutant mice exhibit early hearing loss, especially at higher frequencies, and that loss or malformation of the stereocilia of outer hair cells appears to be a contributing factor. PMID:23996384

Oishi, Naoki; Chen, Jun; Zheng, Hong-Wei; Hill, Kayla; Schacht, Jochen; Sha, Su-Hua

2013-08-31

247

Chloroquine inhibits macrophage tumour necrosis factor-alpha mRNA transcription.  

PubMed Central

Although chloroquine administration in vivo following haemorrhage in mice decreases tumour necrosis factor-alpha (TNF-alpha) release by macrophage (M phi), the mechanism remains unknown. To study this, peritoneal M phi (pM phi) from unmanipulated, sham-operated and post-haemorrhage mice were isolated, treated with 0.13 mg/ml chloroquine for 2 hr, and then stimulated with lipopolysaccharide (LPS) for 48 hr. Pretreatment of pM phi from various groups of mice with chloroquine resulted in 75-90% inhibition of TNF-alpha release, determined by bioassay. Total RNA was isolated from pM phi and murine M phi-derived cell lines (P388D1 and RAW 264.7), stimulated with LPS for 0.5 or 1 hr, respectively, and Northern blot analysis for TNF-alpha mRNA performed. Chloroquine inhibited TNF-alpha mRNA expression without interfering with mRNA stability, suggesting that this agent reduces M phi TNF-alpha release by disrupting TNF-alpha gene transcription. Images Figure 2 Figure 3 Figure 4

Zhu, X; Ertel, W; Ayala, A; Morrison, M H; Perrin, M M; Chaudry, I H

1993-01-01

248

Analysis of Relationship between Tumor Necrosis Factor Alpha Gene (G308A Polymorphism) with Preterm Labor  

PubMed Central

Background: Increased concentrations of tumor necrosis factor alpha (TNF-?) in blood and amniotic fluid are observed in women with preterm delivery (PTD) and TNF-? mutations at ?308 position are associated with higher expression of this gene. Therefore, we compared the frequency of G308A transition in the promoter region of TNF-? gene of women and neonates delivered preterm with the normal subjects. Methods: This cross-sectional study was performed on 135 mothers who were referred for delivery. According to the gestational age, mothers and their neonates were allocated to the case (preterm, 64 subjects) and control (term, 71 subjects) groups. Using the polymerase chain reaction, restrictive fragment length polymorphism (RFLP), genotyping was performed on both maternal peripheral blood and cord blood samples to determine single nucleotide polymorphism in the promoter region of TNF-? gene at ?308. Results: Two mothers in the case group, one mother in the control group and one neonate in the case group had genotyping assays (GA) mutation. All other subjects had normal GG genotype. Frequency of GA mutation was not significantly different between two groups (P = 0.47). Conclusions: There is no significant association between PTD and either maternal or fetal TNF-? ?308 polymorphism and frequency ofGAmutation is not significantly increased in mothers and neonates delivered preterm. It means that the presence of this mutation by itself does not modify the overall risk of PTD. Investigations on the combination of various polymorphisms indifferent genes are recommended to achieve more accurate results.

Jafarzadeh, Lobat; Danesh, Azar; Sadeghi, Marzieh; Heybati, Fateme; Hashemzadeh, Morteza

2013-01-01

249

IgA specific helper factor (alpha HF) in human colostrum.  

PubMed Central

Induction of immunoglobulin secretion by human colostrum was investigated using human peripheral blood lymphocytes (PBL) and Epstein-Barr virus transformed human B lymphoblastoid cells. Stimulation of the cells with colostrum induced IgA plaque forming cells but neither IgG nor IgM plaque forming cells, indicating the occurrence of IgA specific helper factor (alpha HF) in human colostrum. alpha HF activity was eluted into fractions with an apparent molecular weight of about 80 kD by gel filtration, and with a PI range of 5.8 to 6.2 by chromatofocusing. IgA secreted by PBL stimulated with alpha HF had a similar molecular weight distribution to that of IgA in human colostrum. From these results a hypothesis is proposed; IgA-committed B cells in the mammary gland differentiate to plasma cells producing dimeric IgA after stimulation by alpha HF so that the dominant immunoglobulin in human colostrum is IgA.

Shinmoto, H; Kawakami, H; Dosako, S; Sogo, Y

1986-01-01

250

Tumor necrosis factor-alpha triggers mucus production in airway epithelium through an IkappaB kinase beta-dependent mechanism.  

PubMed

Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IkappaB kinase beta (IKKbeta) in mucus synthesis in vitro and in vivo. Tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-alpha stimulation of human epithelial cells resulted in mucus secretion as measured by MUC5AC mRNA and protein. TNF-alpha stimulation induced IKKbeta-dependent p65 nuclear translocation, mucus synthesis, and production of cytokines from epithelial cells. TNF-alpha, but not transforming growth factor-alpha, induced mucus production dependent on IKKbeta-mediated NF-kappaB activation. In vivo, TNF-alpha induced NF-kappaB as determined by whole mouse body bioluminescence. This activation was localized to the epithelium as revealed by LacZ staining in NF-kappaB-LacZ transgenic mice. TNF-alpha-induced mucus production in vivo could also be inhibited by administration into the epithelium of an IKKbeta dominant negative adenovirus. Taken together, our results demonstrated the important role of IKKbeta in TNF-alpha-mediated mucus production in airway epithelium in vitro and in vivo. PMID:16123045

Lora, José M; Zhang, Dong Mei; Liao, Sha Mei; Burwell, Timothy; King, Anne Marie; Barker, Philip A; Singh, Latika; Keaveney, Marie; Morgenstern, Jay; Gutiérrez-Ramos, José Carlos; Coyle, Anthony J; Fraser, Christopher C

2005-08-25

251

Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-alpha increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-alpha activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-alpha treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP-dependent protein kinase A (PKA). Coincubation with TNF-alpha and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF-alpha induces perilipin hyperphosphorylation by activating PKA, TNF-alpha increased intracellular cAMP approximately 1.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-alpha-induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF-alpha-induced lipolysis. Finally, TNF-alpha decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by approximately 50%, delineating a mechanism by which TNF-alpha could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-alpha stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP. PMID:12351429

Zhang, Hui H; Halbleib, Melanie; Ahmad, Faiyaz; Manganiello, Vincent C; Greenberg, Andrew S

2002-10-01

252

Lipopolysaccharide triggers invasive streptococcal disease in mice through a tumour necrosis factor-alpha-dependent mechanism.  

PubMed

Streptococcus pyogenes sometimes induces invasive streptococcal infection, including streptococcal toxic shock syndrome (STSS). Muscular necrosis is one of the peculiar symptoms of invasive streptococcal infection and STSS. We inoculated S. pyogenes into the muscles of mice. To do so, 5 x 10(8) bacteria in 0.2 ml phosphate-buffered saline were injected into the right hind thigh. None of the mice injected with the bacteria showed muscular necrosis and none died. Tumour necrosis factor-alpha (TNF-alpha) and infiltration of leucocytes were detected in the muscles of infected sites, although the condition of the infected mice did not deteriorate after anti-TNF-alpha monoclonal antibody treatment. The infected mice treated intraperitoneally with Escherichia coli lipopolysaccharide (LPS) showed augmentation of bacterial growth, muscular necrosis and death. TNF-alpha was detected in the sera of the infected mice treated with LPS, but not in the muscles of the infected sites. Infiltration of leucocytes into the infected muscle was not observed in the infected mice treated with LPS. Anti-TNF-alpha monoclonal antibody treatment decreased mortality in the infected mice treated with LPS. Moreover, the infected mice treated with recombinant TNF-alpha showed augmentation of muscular necrosis and death. These results suggest that systemic production of TNF-alpha induced by stimulation with LPS inhibits infiltration of leucocytes into the infected site and exacerbates muscular infection, and that TNF-alpha produced in streptococcal infection is not a defence factor for the host. Invasive streptococcal infection and STSS appear to be induced by both S. pyogenes and the host's immune system. PMID:11918696

Diao, Hongyan; Kohanawa, Masashi; Yimin; Nakajima, Hirofumi; Sato, Yuichiro; Minagawa, Tomonori; Nakane, Akio

2002-03-01

253

Tumor necrosis factor ?-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis  

Microsoft Academic Search

ABSTRACT: INTRODUCTION: Tumor necrosis factor-alpha (TNF?) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNF? antagonists in RA is poorly defined. Immunization of DBA\\/1 mice with glucose-6-phosphate isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNF? antagonists, suggesting similar etiology to RA. In this study, we explored TNF?-related mechanisms of

Asuka Inoue; Isao Matsumoto; Yoko Tanaka; Keiichi Iwanami; Akihiro Kanamori; Naoyuki Ochiai; Daisuke Goto; Satoshi Ito; Takayuki Sumida

2009-01-01

254

Corticosterone inhibits expression of the microglial glutamate transporter GLT-1 in vitro.  

PubMed

The present study investigates the effect of the glucocorticoid corticosterone on microglial glutamate transporters in vitro. Microglial cultures obtained from rat cerebral cortex were found to express the excitatory amino acid transporter GLT-1, but not GLAST, and this expression was increased by 1 ng/ml lipopolysaccharide after 12 h of stimulation. This increase has previously been shown to be mediated by tumor necrosis factor-alpha, a cytokine released by microglia during pathological conditions. Furthermore, lipopolysaccharide increased the microglial release of tumor necrosis factor-alpha and 1 microM corticosterone inhibited this effect. Corticosterone also inhibited the lipopolysaccharide-induced increase of the GLT-1 expression as well as the expression in non-activated cells. The effect of corticosterone on the GLT-1 expression was dose dependent and accompanied by similar effects on the microglial glutamate uptake capacity. Additionally, exogenous tumor necrosis factor-alpha was found to counteract the effect of corticosterone on microglial GLT-1 expression. The effect of corticosterone appeared to be glucocorticoid receptor specific since 10 microM of the glucocorticoid receptor antagonist mifepristone inhibited the effect. Thus, corticosterone decreased the microglial uptake of glutamate by decreasing the expression of glutamate transporters, probably due to the inhibited microglial tumor necrosis factor-alpha release. These results provide insights into the mechanisms behind microglial glutamate transporter expression during pathological conditions, and contribute to the debate about the beneficial or harmful effects of glucocorticoids. PMID:16473474

Jacobsson, J; Persson, M; Hansson, E; Rönnbäck, L

2006-02-13

255

The role of transforming growth factor alpha in rat craniofacial development and chondrogenesis.  

PubMed Central

To explore the possible role of transforming growth factor alpha (TGF-alpha) in craniofacial development, its expression in the craniofacial region of rat embryos from embryonic day (d) 9 to d 20 was examined by in situ hybridisation and immunostaining. The TGF-alpha transcripts were first detected in the neural fold of embryonic d 9 and 10 embryos. In the craniofacial region, the TGF-alpha transcripts were not detected until embryonic d 16 in mesenchyme surrounding the olfactory bulb, within the olfactory bulb, the nasal capsule, vomeronasal organ, and vibrissal follicle. In addition, TGF-alpha message was detected in mesenchyme in the vicinity of Meckel's cartilage, and in the dental epithelium and lamina. This expression pattern of TGF-alpha transcripts persisted until embryonic d 17 but disappeared by d 18. The presence of TGF-alpha protein largely coincided with TGF-alpha message although, unlike the message, it persisted throughout later embryogenesis in the craniofacial region. The possible function of TGF-alpha in chondrogenesis was explored by employing the micromass culture technique. Cartilage nodule formation in mesenchymal cells cultured from rat mandibles in the presence of TGF-alpha was significantly inhibited. This inhibitory effect of TGF-alpha on chondrogenesis was reversed by addition of antibody against the EGF receptor, which crossreacts with the TGF-alpha receptor. The inhibitory effect of TGF-alpha on chondrogenesis in vitro was further confirmed by micromass culture using mesenchymal cells from rat embryonic limb bud. Taken together, these results demonstrate the involvement of TGF-alpha in chondrogenesis during embryonic development, possibly by way of a specific inhibition of cartilage formation from mesenchymal precursor cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 9

Huang, L; Solursh, M; Sandra, A

1996-01-01

256

Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells  

PubMed Central

Tumor necrosis factor-alpha (TNF-?) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-? on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-? significantly increased the total EM and decreased the estrone (E1) / 17-? estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-? directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer.

Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud; Kilic, Gokhan; Veenstra, Timothy; Saeed, Muhammad; Wagih, Mohamed; Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama

2012-01-01

257

Reduction of concanavalin A-induced expression of interferon-gamma by bovine lactoferrin in feline peripheral blood mononuclear cells.  

PubMed

Lactoferrin (LF), a glycoprotein present in milk, mucosal secretions and neutrophils, contributes to host defense and immunomodulation. In the present study, we investigated the effect of bovine LF (bLF) on cytokine messenger RNA (mRNA) expression in concanavalin A (ConA)-stimulated feline peripheral blood mononuclear cells (PBMC). Semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and real-time PCR showed a ConA-induced increase of interferon-gamma (IFN-gamma) mRNA expression but not of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and IL-12 p40 mRNA in feline PBMC. This ConA-induced increase of IFN-gamma mRNA expression was inhibited by addition of bLF not only 30 min before ConA stimulation but also 10, 20 and 40 min after ConA stimulation. Western blotting showed that protein tyrosine kinase (PTK) and extracellular signal-regulated kinase (ERK) in feline PBMC were activated within 10 min after the ConA stimulation and that the activation of both kinases had almost disappeared by 40 min after stimulation. Moreover, the ConA-induced IFN-gamma mRNA expression was partly prevented by genistein, a global PTK inhibitor, and PD-98059, an ERK inhibitor, respectively. These results suggest that bLF is able to inhibit the ConA-induced IFN-gamma mRNA expression by abrogation of intracellular signaling activated after interaction between ConA and its receptor. PMID:15797477

Kobayashi, Saori; Sato, Reeko; Inanami, Osamu; Yamamori, Tohru; Yamato, Osamu; Maede, Yoshimitsu; Sato, Jun; Kuwabara, Mikinori; Naito, Yoshihisa

2005-05-01

258

Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation.  

PubMed

Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor necrosis factor alpha was determined by quantitative reverse transcription-polymerase chain reaction in alveolar macrophages. Rac1 activity was increased in lungs from septic animals, and NSC23766 significantly decreased pulmonary activity of Rac1 induced by CLP. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation, and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. Moreover, NSC23766 abolished the sepsis-evoked elevation of messenger RNA levels of CXC chemokines and tumor necrosis factor alpha in alveolar macrophages. Rac1 inhibition decreased the CLP-induced increase in plasma levels of high mobility group protein B1 and interleukin 6, indicating a role of Rac1 in systemic inflammation. In conclusion, our results demonstrate that Rac1 signaling plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis. Thus, targeting Rac1 activity might be a useful strategy to protect the lung in abdominal sepsis. PMID:23545410

Hwaiz, Rundk; Hasan, Zirak; Rahman, Milladur; Zhang, Su; Palani, Karzan; Syk, Ingvar; Jeppsson, Bengt; Thorlacius, Henrik

2013-03-15

259

Expression kinetics of interferon and interferon-induced genes in Atlantic salmon (Salmo salar) following infection with infectious pancreatic necrosis virus and infectious salmon anaemia virus.  

PubMed

Infectious pancreatic necrosis virus (IPNV) and infectious salmon anaemia virus (ISAV) are economically important pathogens of the salmonid aquaculture industry. Atlantic salmon were challenged by intraperitoneal injection (i.p.) with either virus followed by time-course sampling. Cohabiting fish in the IPNV challenge were also sampled. Kidney tissue was analysed using a TaqMan real-time PCR assay to measure the expression of a range of host immune genes in relation to the endogenous control, elongation factor 1 alpha (ELF). Host genes measured included Mx, type I and type II interferon (IFN), gammaIFN induced protein (gammaIP), interleukin-1 beta (IL-1beta) and tumour necrosis factor alpha (TNF-alpha). Viral levels were also measured. In i.p. injected fish, both viruses greatly induced expression of Mx, gammaIP, type I and type II IFN by day 6 post-infection, however only ISAV caused substantial mortality. Some differences between the expression kinetics produced by both viruses were noted. Infection with ISAV increased IL-1beta expression following day 6, but no effect was seen in fish infected with IPNV. Neither virus induced TNF-alpha expression. This study confirms the presence of both type I and type II IFN responses and their induced genes in Atlantic salmon upon infection with an orthomyxovirus and a birnavirus. PMID:16806972

McBeath, A J A; Snow, M; Secombes, C J; Ellis, A E; Collet, B

2006-05-23

260

Disaccharide esters screened for inhibition of tumor necrosis factor-alpha release are new anti-cancer agents.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine playing a part in various pathological states. Non-toxic inhibitors of TNF-alpha release are thought to be promising agents for cancer prevention. We found that the acetone fraction of the tobacco leaf surface lipid containing glucose esters and sucrose esters inhibited both TNF-alpha release from BALB/3T3 and KATO III cells induced by okadaic acid and tumor promotion by okadaic acid on mouse skin initiated with 7,12-dimethylbenz(a)anthracene (DMBA). Next, we investigated the inhibition of TNF-alpha release with synthetic disaccharide esters, such as 6,6'-di-O-alkanoyl-alpha, alpha-trehaloses (6,6'-diester-trehaloses), 4,4'-di-O-alkanoyl-alpha, alpha-trehaloses (4,4'-diester-trehaloses) and 6,6'-diamino-6,6'-dideoxy-N,N'-dialkanoyl-alpha, alpha-trehaloses (6,6'-diamide-trehaloses) bearing fatty acids of various chain lengths, and n-dodecyl-beta-D-maltoside as a disaccharide monoester. 6,6'-Diester-trehaloses and 4,4'-diester-trehaloses of C8 to C12 fatty acids, 6,6'-diamide-trehaloses of C8 to C14 fatty acids, and n-dodecyl-beta-D-maltoside all inhibited TNF-alpha release in a dose-dependent manner. The IC50 values are 7.4-14.8 microM for 6,6'-diester-trehaloses (C8 to C12), 14.6-21.6 microM 4,4'-diester-trehaloses (C8 to C12), 2.9-15.0 microM for 6,6'-diamide-trehaloses (C8 to C14) and 23 microM for dodecyl-beta-D-maltoside. Both 6,6'-di-O-octanoyl-alpha, alpha-trehalose (C8, designated as SS555) and n-dodecyl-beta-D-maltoside (C12) inhibited tumor promotion by okadaic acid on mouse skin initiated with DMBA. Percentages of tumor-bearing mice in week 15 of tumor promotion were reduced from 60.0 to 13.3 with SS555, and to 46.7 with n-dodecyl-beta-D-maltoside. Moreover, SS555 inhibited TNF-alpha gene expression mediated through inhibition of AP-1 activation, but not NF-kappa B activation. This paper reports that diester-trehaloses of C8 to C12 fatty acids and mimics of disaccharide monoesters such as n-dodecyl-beta-D-maltoside appear to be potential cancer-preventive agents of a new type. PMID:10429660

Okabe, S; Suganuma, M; Tada, Y; Ochiai, Y; Sueoka, E; Kohya, H; Shibata, A; Takahashi, M; Mizutani, M; Matsuzaki, T; Fujiki, H

1999-06-01

261

Dissecting Cellulitis of the Scalp Responding to Intravenous Tumor Necrosis Factor-alpha Antagonist  

PubMed Central

The authors present the case of a 30-year-old male patient with a severe and long-standing dissecting cellulitis of the scalp. The disease did not respond to conventional treatment, including oral antibiotics, isotretinoin, and prednisolone. Quality of life was significantly impaired. After introduction of anti-tumor necrosis factor-alpha treatment (infliximab), the malodorous discharge stopped, inflammation was reduced significantly, nodules became flat, and pain decreased. The treatment was well tolerated although he developed a temporary psoriasiform rash after the second intravenous infusion. In conclusion, anti-tumor necrosis factor-alpha treatment is a new therapeutic option in this severe and recalcitrant disorder.

Wollina, Uwe; Gemmeke, Astrid; Koch, Andre

2012-01-01

262

Inactivation of Membrane Tumor Necrosis Factor Alpha by Gingipains from Porphyromonas gingivalis  

PubMed Central

Gingipains are cysteine proteinases produced by Porphyromonas gingivalis, a major causative bacterium of adult periodontitis. They consist of arginine-specific (HRgpA and RgpB) and lysine-specific (Kgp) proteinases. Gingipains strongly affect the host defense system by degrading some cytokines, components of the complement system, and several immune cell receptors. In an in vitro model, gingipains were shown to degrade soluble tumor necrosis factor alpha (TNF-?). However, since membrane TNF-? shows strong biological activity, especially in local inflammatory lesions, it was worth investigating whether gingipains might also destroy membrane TNF-? and limit its biological activities. To avoid a possible influence of gingipains on ADAM17, the secretase of TNF-?, the majority of experiments were performed using ADAM17?/? fibroblasts stably transfected with cDNA of human pro-TNF-? (ADAM17?/? TNF+). Arginine-specific gingipains (Rgp's) strongly diminished the level of TNF-? on the cell surface as measured by flow cytometry, and this process was not accompanied by an increased concentration of soluble TNF-? in the culture medium. Degradation of membrane TNF-? by Rgp's correlated with a strong decrease in TNF-?-mediated biological activities of ADAM17?/? TNF+ cells. First, the activation state of transcription factor NF-?B was suppressed; second, the cells were no longer able to induce apoptosis in HL-60 cells. Kgp was also able to cleave membrane TNF-?, but its effect was much weaker than that of Rgp's. Gingipains also limited the binding of native TNF-? to the target cells. Thus, gingipains are able not only to cleave soluble TNF-? but also to destroy the membrane form of the cytokine, which may additionally dysregulate the cytokine network.

Mezyk-Kopec, Renata; Bzowska, Malgorzata; Potempa, Jan; Bzowska, Monika; Jura, Natalia; Sroka, Aneta; Black, Roy A.; Bereta, Joanna

2005-01-01

263

A Role for Tumor Necrosis Factor-Alpha (TNF?) in Experimental Bacillus cereus Endophthalmitis Pathogenesis  

PubMed Central

Purpose To determine the contribution of tumor necrosis factor-alpha (TNF?)e pathogenesis of experimental Bacillus cereus endophthalmitis. Methods Experimental B. cereus endophthalmitis was induced in wild-type control (B6.129F1) or age-matched homozygous TNF? knockout mice (TNF??/?, B6.129S6-Tnftm1Gk1/J). At various times postinfection, eyes were analyzed by electroretinography, and harvested for quantitation of bacteria, myeloperoxidase, proinflammatory cytokines and chemokines, and histological analysis. Results B. cereus replicated more rapidly in eyes of TNF??/? mice compared to that of B6.129F1 eyes. Retinal function decreased more rapidly in eyes of TNF??/? mice compared to that of B6.129F1 eyes. Retinal layers were not as structurally intact at 6 and 12 h postinfection in TNF??/? eyes compared to that of B6.129F1 eyes. Histological analysis suggested less PMN infiltration in the vitreous of TNF??/? mice than in B6.129F1 mice. B6.129F1 eyes also had greater myeloperoxidase concentrations than did eyes of TNF??/? mice. In general, concentrations of proinflammatory cytokines and chemokines (IL-1? IL-6, and MIP-1?) were greater in eyes of TNF??/? mice than in B6.129F1 eyes. Conclusions TNF? is important to intraocular pathogen containment by PMN during experimental B. cereus endophthalmitis. In the absence of TNF ?, less PMN migrated into the eye, facilitating faster bacterial replication and retinal function loss. Although greater concentrations of proinflammatory cytokines were synthesized in the absence of TNF?, the resulting inflammation was less, and an equally devastating course of infection occurred.

Ramadan, R.T.; Moyer, A.L.; Callegan, M.C.

2008-01-01

264

Captopril inhibits the production of tumor necrosis factor-alpha by human mononuclear cells in patients with congestive heart failure.  

PubMed

To study the effects of captopril on tumor necrosis factor-alpha produced by peripheral blood mononuclear cells (PBMC) of patients with congestive heart failure (CHF), we determined the TNF-alpha concentrations of culture supernatants of PBMC with and without catopril in 74 CHF patients with various heart diseases. The results showed that the supernatants concentrations of TNF-alpha in cultured PBMC (PBMC-TNF-alpha) were significantly increased in non-cachetic and cachetic CHF patients, and even higher in cachetic CHF patients, as compared with the controls (i.e., patients with New York Heart Association CHF classification I). The PBMC-TNF-alpha was significantly inhibited by captopril. These results demonstrate that the expression of TNF-alpha in PBMC is increased and can be inhibited by captopril in patients with CHF, especially in those accompanied by cachexia. This suggests that the immunomodulatory effects of captopril may contribute to its beneficial effects in heart failure patients. PMID:11165202

Zhao, S P; Xie, X M

2001-02-01

265

Constitutive shedding of the amyloid precursor protein ectodomain is up-regulated by tumour necrosis factor-alpha converting enzyme.  

PubMed Central

The amyloid precursor protein (APP) of Alzheimer's disease is a transmembrane protein that is cleaved within its extracellular domain, liberating a soluble N-terminal fragment (sAPP alpha). Putative mediators of this process include three members of the ADAM (a disintegrin and metalloprotease) family, ADAM9, ADAM10 and ADAM17/TACE (tumour necrosis factor-alpha converting enzyme). Tumour necrosis factor-alpha protease inhibitor (TAPI-1), an inhibitor of ADAMs, reduced constitutive and muscarinic receptor-stimulated sAPP alpha release in HEK-293 cells stably expressing M3 muscarinic receptors. However, the former was less sensitive to TAPI-1 (IC(50)=8.09 microM) than the latter (IC(50)=3.61 microM), suggesting that these processes may be mediated by different metalloproteases. Constitutive sAPP alpha release was increased several-fold in cells transiently transfected with TACE, and this increase was proportional to TACE expression. In contrast, muscarinic-receptor-activated sAPP alpha release was not altered in TACE transfectants. TACE-dependent constitutive release of co-transfected APP(695) was inhibited by TAPI-1 with an IC(50) of 0.92 microm, a value significantly lower than the IC(50)s for inhibition of either constitutive or receptor-regulated sAPP alpha shedding mediated by endogenous secretases. The results indicate that TACE is capable of catalysing constitutive alpha-secretory cleavage of APP, but it is likely that additional members of the ADAM family mediate endogenous constitutive and receptor-coupled release of sAPP alpha in HEK-293 cells.

Slack, B E; Ma, L K; Seah, C C

2001-01-01

266

Tumor Necrosis Factor Alpha, Interleukin 1 and Related Cytokines in Brain Development: Normal and Pathological  

Microsoft Academic Search

Microglia and astrocytes produce several cytokines including interleukin 1 (IL1) and tumor necrosis factor alpha (TNF?), which have pleiotropic effects in the immune and nervous systems. Recent evidence has come to light that they play a role in damage in the central nervous system. This indeed may be the result of overproduction of these factors as the consequence of trauma

Jean E. Merrill

1992-01-01

267

Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis  

Microsoft Academic Search

The production of tumour necrosis factor alpha (TNF alpha) and interleukin-6 by human antral mucosa during short term culture in vitro has been measured by enzyme linked immunosorbent assay. TNF alpha and interleukin-6 concentrations in culture supernatants were significantly greater (p less than 0.001) in patients infected with Helicobacter pylori, all of whom had chronic gastritis, than in patients who

J E Crabtree; T M Shallcross; R V Heatley; J I Wyatt

1991-01-01

268

Gemella morbillorum Bacteremia after Anti-Tumor Necrosis Factor Alpha as Acne Inversa Therapy  

PubMed Central

We present a case of fever, brain abscesses, and Gemella morbillorum bacteremia after anti-tumor necrosis factor alpha (TNF-?) therapy in a 21-year-old acne inversa patient currently taking long-term dapsone. To the best of our knowledge, this is the first report describing such a case. During antimicrobial therapy, the patient developed systemic varicella infection with severe thrombocytopenia.

Vossen, Matthias G.; Gattringer, Klaus B.; Khalifeh, Neda; Koreny, Maria; Spertini, Verena; Mallouhi, Ammar; Willeit, Markus; Volc-Platzer, Beatrix; Asboth, Friederike; Graninger, Wolfgang; Thalhammer, Florian

2012-01-01

269

Involvement of H-Ras and reactive oxygen species in proinflammatory cytokine-induced matrix metalloproteinase-13 expression in human articular chondrocytes.  

PubMed

Proinflammatory cytokines such as interleukin-1 beta (IL-1?) and tumor necrosis factor alpha (TNF-?) enhance degradation of cartilage-specific, type II collagen by matrix metalloproteinase-13 (MMP-13). We investigated the previously unknown role of H-Ras and reactive oxygen species (ROS) in the cytokine induction of MMP-13 gene expression in human articular chondrocytes by using pharmacological inhibitors, RNA interference (RNAi) and antioxidants. Manumycin A, an inhibitor of H-Ras farnesylation by farnesyltransferase, suppressed IL-1?- and TNF-?-induced MMP-13 mRNA and protein expression. Small interfering RNA (siRNA)-mediated H-Ras silencing down-regulated MMP-13 mRNA and protein induction by IL-1? and TNF-?. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase/NOX) inhibitor, diphenyleneiodonium (DPI) suppressed cytokine-induced MMP-13 expression and superoxide production. Apocynin, another NOX inhibitor, also diminished MMP-13 induction. Deoxyglucose an antimetabolite of glucose metabolism reduced MMP-13 increase. Role of NOX-mediated ROS production was reaffirmed by the observation that the antioxidants, trolox, nordihydroguaiaretic acid (NDGA), quercetin and resveratrol downregulated cytokine-induced MMP-13 mRNA and protein expression. These results provide strong pharmacological and genetic evidence for the implication of H-Ras and NADPH oxidase-generated superoxide production in MMP-13 gene regulation by IL-1? and TNF-?. These proteins could be potentially targeted for therapeutic inhibition of MMP-13-driven cartilage erosion by using H-Ras and NOX inhibitors and antioxidants. PMID:21211511

Ahmad, Rasheed; Sylvester, Judith; Ahmad, Mushtaq; Zafarullah, Muhammad

2011-01-03

270

Effects of Puerariae Radix Extract on Endotoxin Receptors and TNF-? Expression Induced by Gut-Derived Endotoxin in Chronic Alcoholic Liver Injury  

PubMed Central

Kudzu (Pueraria lobata) is one of the earliest medicinal plants used to treat alcohol abuse in traditional Chinese medicine for more than a millennium. However, little is known about its effects on chronic alcoholic liver injury. Therefore, the present study observed the effects of puerariae radix extract (RPE) on chronic alcoholic liver injury as well as Kupffer cells (KCs) activation to release tumor necrosis factor alpha (TNF-?) induced by gut-derived endotoxin in rats and macrophage cell line. RPE was observed to alleviate the pathological changes and lipids deposition in liver tissues as well as the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic gamma-glutamyl transpeptidase (GGT) activity. Meanwhile, RPE inhibited KCs activation and subsequent hepatic TNF-? expression and downregulated the protein expression of endotoxin receptors, lipopolysaccharide binding protein (LBP), CD14, Toll-like receptor (TLR) 2, and TLR4 in chronic alcohol intake rats. Furthermore, an in vitro study showed that RPE inhibited the expression of TNF-? and endotoxin receptors, CD14 and TLR4, induced by LPS in RAW264.7 cells. In summary, this study demonstrated that RPE mitigated liver damage and lipid deposition induced by chronic alcohol intake in rats, as well as TNF-? release, protein expression of endotoxin receptors in vivo or in vitro.

Peng, Jing-Hua; Cui, Tuan; Sun, Zhao-Lin; Huang, Fu; Chen, Liang; Xu, Lin; Feng, Qin; Hu, Yi-Yang

2012-01-01

271

Anti-tumor necrosis factor-alpha therapy provokes latent leishmaniasis in a patient with rheumatoid arthritis.  

PubMed

It has been reported that anti-tumor necrosis factor-alpha therapy increases the risk of opportunistic infections including rare case reports of leishmaniasis. Here we report a case of latent cutaneous leishmaniasis, which was provoked by anti-tumor necrosis factor-alpha therapy in a patient with rheumatoid arthritis. PMID:19429808

Franklin, Gillian; Greenspan, Joel; Chen, Sheng

2009-01-01

272

Activation-Induced Cytidine Deaminase Expression in Gastric Cancer  

Microsoft Academic Search

Helicobacter pylori increases the risk of gastric cancer development and triggers aberrant expression of activation-induced cytidine deaminase (AID). The goal of the present study was to investigate whether AID expression is involved in the development or progression of gastric cancer and the nuclear expression of p53 protein in cancer cells. We examined the expression pattern of the AID and p53

Chang Jae Kim; Jae Hwi Song; Yong Gu Cho; Zhang Cao; Su Young Kim; Suk Woo Nam; Jung Young Lee; Won Sang Park

2007-01-01

273

Mycoplasma arthritidis-derived superantigen induces proinflammatory monokine gene expression in the THP-1 human monocytic cell line.  

PubMed Central

Soluble factors produced by Mycoplasma arthritidis play an important role in the pathology of arthritis in rodents, which closely resembles human rheumatoid arthritis. At least one of the products of these microorganisms, M. arthritidis-T cell mitogen (MAM), has biological activities in common with superantigens. These superantigens activate T cells in a V beta-restricted fashion, and this response is strictly dependent on the presence of major histocompatibility complex (MHC) class II-positive cells. In the present study, we have examined the ability of MAM to induce proinflammatory monokine (interleukin 1 beta [IL-1 beta] and tumor necrosis factor alpha [TNF-alpha]) gene expression in the THP-1 monocytic cell line. Treatment of these cells (which express a very low level of HLA-DR molecules) with gamma interferon (INF-gamma) induced HLA-DR, -DQ, and -DP molecules and enabled them to respond to MAM in a dose-dependent manner, resulting in an increase in the level of steady-state mRNA for IL-1 beta and TNF-alpha. Stimulation of the U937 monocytic cell line (MHC class II-negative even after INF-gamma treatment) with MAM did not induce either IL-1 beta or TNF-alpha transcription. Moreover, MAM adsorption on Raji (MHC class II-positive) cells resulted in the loss of its cytokine-inducing activity to induce monokine gene expression. These findings demonstrate clearly that MAM induces monokine gene expression following interaction with MHC class II molecules. Pretreatment of INF-gamma-treated THP-1 cells with the transcription inhibitor actinomycin D prevented the induction of monokine mRNA, whereas cycloheximide superinduced mRNA after stimulation with MAM. Finally, our results, obtained with protein tyrosine kinase inhibitors and antiphosphotyrosine Western blotting (immunoblotting), indicate that protein tyrosine kinase is involved in MAM-induced IL-1 beta and TNF-alpha gene expression in the THP-1 monocytic cell line. The capacity of MAM to induce proinflammatory cytokine transcription in monocytes via MHC class II molecules can be one pathway of MAM contribution to autoimmune diseases. Images

al-Daccak, R; Mehindate, K; Hebert, J; Rink, L; Mecheri, S; Mourad, W

1994-01-01

274

Characterization of a tumor necrosis factor. alpha. (TNF-. alpha. ) inhibitor: Evidence of immunological cross-reactivity with the TNF receptor  

SciTech Connect

Previous studies have shown that urine of febrile patients contains a tumor necrosis factor {alpha} inhibiting activity (TNF-{alpha} Inh) when tested in a cytotoxicity assay using the tumor necrosis factor {alpha} (TNF-{alpha})-susceptible cell line L929. In the present study, the authors investigated the relationship between the TNF-{alpha} Inh and a potential soluble form of the receptor, as the former has been shown to block TNF-{alpha} activities by binding to the ligand. They demonstrate that human TNF-{alpha} is affected to a greater extent than is murine TNF-{alpha}. This species specificity of the inhibitor correlates with the binding studies of TNF receptor interactions already reported. They raised a polyclonal antibody to TNF-{alpha} Inh that neutralizes its activity and does not recognize TNF-{alpha}. Solubilized cross-linked {sup 125}I-labeled TNF-{alpha} receptor complex could be immunoprecipitated by using either anti-TNF-{alpha} or anti-TNF-{alpha} Inh antibody, suggesting immunological cross-reactivity between the receptor and the inhibitor. By using fluorescein isothiocyanate-coupled TNF-{alpha}, it was possible to visualize by fluorescence-activated cell sorter analysis the TNF-{alpha} receptor on phytohemagglutinin/interleukin 2-activated T cells. A similar increase of immunofluorescence intensity of the activated T cells was observed by using anti-TNF-{alpha} Inh antibody revealed with a fluorescein isothiocyanate-coupled goat anti-rabbit IgG1 conjugate, suggesting that the TNF-{alpha} Inh is also expressed as a membrane protein. Taken together, their results suggest that the TNF-{alpha} Inh originally described might be a soluble form of the TNF receptor itself.

Seckinger, P.; Zhang, Jianhua; Hauptmann, B.; Dayer, J.M. (Hopital Cantonal Universitaire, Geneva (Switzerland))

1990-07-01

275

Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1.  

PubMed Central

Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) are produced by leukocytes and play a role in immune responses. They also function in normal brain physiology as well as in pathological conditions within the central nervous system, where they are produced by brain macrophages (microglia) and brain astrocytes. In this study, we document the ability of human immunodeficiency virus type 1 (HIV-1) to induce TNF alpha and IL-1 in primary rat brain cultures. While productive infection did not occur in these cells, it was not required for cytokine induction. Using monocyte/macrophage-tropic (JRFL) and T-cell-tropic (IIIB) strains of HIV-1, we were able to induce cytokines in both microglia and astrocytes. In addition to whole virus, recombinant envelope proteins also induced these cytokines. The induction of IL-1 and TNF alpha could be blocked by a panel of antibodies recognizing epitopes in the gp120 and gp41 areas of the envelope. Soluble recombinant CD4 did not block TNF alpha and IL-1 production. If TNF alpha and IL-1 can be induced in brain tissue by HIV-1, they may contribute to some of the neurologic disorders associated with AIDS. Images

Merrill, J E; Koyanagi, Y; Zack, J; Thomas, L; Martin, F; Chen, I S

1992-01-01

276

Induction of tumor necrosis factor alpha in murine macrophages with various strains of Coxiella burnetii and their lipopolysaccharides.  

PubMed

The ability of various strains of Coxiella burnetii (C.b.) and their phase I and II lipopolysaccharides (LPSs) to induce tumor necrosis factor alpha (TNF-alpha) in peritoneal Balb/c mouse macrophages in vitro was investigated. Considerable differences in the induction ability were observed in dependence on the strain applied. In a TNF-alpha bioassay, the most effective inducers were both corpuscles and LPSs of the strains Priscilla and Scurry, followed by Nine Mile, Luga, and Henzerling I. In contrast, in ELISA, the most effective inducers were LPSs of the strains Luga and Henzerling, followed by Nine Mile, Priscilla, and Scurry. The role of toll-like receptor 4 (TLR4) in the induction was confirmed by the use of C3H/HeJ mouse macrophages. Thus, the induction of TNF-alpha was much higher in Balb/c mouse macrophages than that in TLR4-deficient C3H/HeJ mouse macrophages. Differences in the results of the bioassay and those of ELISA suggest a role of another secreted factor(s) induced with C.b. in murine macrophages that could act synergically with TNF-alpha in L929 cells in the bioassay. The observed differences in TNF-alpha induction might play a role in the pathobiology of Q fever. PMID:16808326

Kubes, M; Kuzmová, Z; Gajdosová, E; Ihnatko, R; Mucha, V; Toman, R; Kovácová, E

2006-01-01

277

Temporal effect of tumor necrosis factor alpha on murine macrophages infected with Mycobacterium avium.  

PubMed Central

Members of the Mycobacterium avium complex are a family of bacteria that persist within macrophages in the face of an immune response. Elimination of these organisms is likely due to cytokine-induced macrophage activation. Because macrophage activation by tumor necrosis factor alpha (TNF-alpha) appears critical for killing of intracellular M. avium, early downregulation of TNF-alpha levels in infected macrophages has been suggested as a survival mechanism for virulent strains of M. avium. We examined the relationship between TNF-alpha and growth of M. avium strains of differing virulence, as measured by their ability to grow in murine bone marrow-derived macrophages. When exogenous TNF-alpha was added immediately following macrophage infection, significant growth inhibition of virulent M. avium strains was observed. If TNF-alpha addition was delayed by 24 h or more, growth inhibition was abrogated. To determine if early downregulation of TNF-alpha levels could explain the differential growth of virulent and avirulent strains, levels of TNF-alpha and prostaglandin E2 (PGE2), which has been shown to suppress TNF-alpha production in uninfected macrophages, were quantified over time. Upregulation of both TNF-alpha and PGE2, as measured by enzyme-linked immunosorbent assay, was evident by 6 h postinfection, indicating that the ability of M. avium to replicate in macrophages was not directly correlated with early downregulation of TNF-alpha production. However, TNF-alpha bioactivity, as measured by cytotoxicity, was significantly decreased in virulent M. avium strains at all time periods examined. Treatment of infected macrophages with gamma interferon immediately after infection resulted in significantly increased levels of nitric oxide but did not affect the growth of virulent M. avium strains. These results suggest that while significant levels of TNF-alpha are present in supernatants from all M. avium strains, levels of biologically active TNF-alpha are significantly reduced in supernatants from virulent M. avium strains. Preliminary results suggest that upregulation of the soluble p75 TNF receptor may be one mechanism by which TNF-alpha bioactivity reduction occurs.

Eriks, I S; Emerson, C L

1997-01-01

278

Cholangitis: bacterial virulence factors that facilitate cholangiovenous reflux and tumor necrosis factor-alpha production.  

PubMed

In previous studies we noted that biliary bacteria produce slime and possess P1-fimbriae. The presence of gram-negative bacteria killed by complement correlated with serious biliary infections and induced more tumor necrosis factor-alpha (TNF-alpha) production in sera, suggesting a role for cytokine production and complement activation in biliary sepsis. This study examined bacterial virulence factors that facilitate cholangiovenous reflux (CVR) and TNF-alpha production in a rat model. Twenty-one biliary bacteria and two stool isolates were tested for slime production, sensitivity to complement killing, and hemolysin production. 10(7) Bacterial colony-forming units/ml (or saline control) were injected retrograde into the common bile ducts of Sprague-Dawley rats at a pressure of 30 cm H(2)O. Blood was obtained at 5 and 60 minutes after infusion for bacterial culture and TNF-alpha assay, respectively. The magnitude of slime production correlated inversely with the magnitude of bacterial CVR. Average bacterial colony-forming units were 1.4 x 10(5), 6.8 x 10(4), or 2.1 x 10(3) for bacteria with slime production 0 to 10, 11 to 99, or more than 100, respectively (P < 0.0001, analysis of variance). CVR was greater for serum-resistant bacteria (1.2 x 10(5) vs. 5.5 x 10(4) [P = 0.007, resistant vs. sensitive]), but TNF-alpha production was greater in serum-sensitive bacteria. TNF-alpha production as a function of bacterial reflux followed a logarithmic curve (R(2) = 0.75) for serum-sensitive bacteria but was linear (R(2) = 0.60) for serum-resistant bacteria. These data show how specific virulence factors explain why some bacterial species colonize without causing illness, whereas others colonize and cause sepsis. Although slime production was necessary for colonization, too much slime inhibited CVR. Although complement killing cleared bacteria from the circulation, it was also associated with increased TNF-alpha production, which can lead to septic manifestations. The most virulent bacterial species (from patients with sepsis) were killed by complement, but they still had significant CVR and were associated with increased TNF-alpha production. PMID:12600443

Stewart, Lygia; Oesterle, Adair L; Grifiss, J McLeod; Jarvis, Gary A; Way, Lawrence W

2003-02-01

279

Cytomegalovirus colitis in a patient with Behcet's disease receiving tumor necrosis factor alpha inhibitory treatment  

PubMed Central

Anti-tumor necrosis factor alpha (TNF-?) inhibitors are effective in the treatment of various inflammatory rheumatic conditions. Increased risks of serious infections are the major issues concerning the long-term safety of these agents. We present a case of a young male Behcet’s patient whose disease was complicated by cytomegalovirus (CMV) colitis. Colitis started 10 d after the third Infliximab dose and responded to the cessation of TNF blocking treatment and administration of ganciclovir. Tumor necrosis factor alpha and interferon gamma act at several levels in combating viral infections. CMV infections should be kept in mind and included in the differential diagnosis of severe gastrointestinal symptoms in patients receiving anti-TNF agents.

Sari, Ismail; Birlik, Merih; Gonen, Can; Akar, Servet; Gurel, Duygu; Onen, Fatos; Akkoc, Nurullah

2008-01-01

280

Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase.  

PubMed Central

The potential involvement of reactive oxygen species in the expression of genes involved in immune response was examined in mesangial cells. Tumor necrosis factor (TNF-alpha) and aggregated (aggr.) IgG increased mRNA levels for the monocyte chemoattractant protein, JE/MCP-1, and the colony-stimulating factor, CSF-1. Scavengers for free radicals such as di- and tetra-methylthiourea (DMTU and TMTU) attenuated the increase in mRNA levels in response to TNF-alpha and aggr. IgG. Generation of superoxide anion by xanthine oxidase and hypoxanthine increased mRNA levels of these genes, but exogenous H2O2 did not. Addition of NADPH to activate a membrane-bound NADPH-oxidase generated superoxide and caused a dose-dependent increase in mRNA levels and further enhanced the stimulation by TNF-alpha or aggr. IgG. An inhibitor of NADPH-dependent oxidase 4'-hydroxy-3'-methoxy-acetophenone attenuated the rise in mRNA levels in response to TNF-alpha and aggr. IgG. By nuclear run-on experiments TNF-alpha, aggr. IgG and NADPH increased the transcription rates for JE/MCP-1 and CSF-1, effects inhibited by TMTU. We conclude that generation of reactive oxygen species, possibly by NADPH-dependent oxidase, are involved in the induction of the JE/MCP-1 and CSF-1 genes by TNF-alpha and IgG complexes. The concerted expression of leukocyte-directed cytokines represents a general response to tissue injury. Images

Satriano, J A; Shuldiner, M; Hora, K; Xing, Y; Shan, Z; Schlondorff, D

1993-01-01

281

Differential regulation of tumour necrosis factor-alpha mRNA degradation in macrophages by interleukin-4 and interferon-gamma.  

PubMed Central

Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) have been reported previously to mediate similar as well as antagonistic effects on murine macrophage functions. One effect common to both is the enhancement of tumour necrosis factor-alpha (TNF-alpha) secretion in macrophages. To assess further the effects of these two lymphokines on macrophage TNF-alpha production, we investigated the role of these lymphokines in the induction and stability of TNF-alpha messages along with interleukin-1 (IL-1) as a comparison. IFN-gamma and IL-4 increased lipopolysaccharide (LPS)-induced TNF-alpha, IL-1 steady-state message levels. In contrast to IL-1 messages, whose degradation was not significantly affected by either lymphokine, the stability of TNF-alpha messages differed after IFN-gamma and IL-4 treatment. Although IL-4 treatment increased the TNF-alpha transcription rate, an increase in the degradation rate of TNF-alpha mRNA in the IL-4-treated cells resulted in a lower level of steady-state mRNA than in the IFN-gamma-treated cells. Additionally, a 18,000 MW cytoplasmic factor was found to have specific binding activity to the AU-rich sequences of the TNF-alpha message in peritoneal macrophages. Although the binding activity of this factor was not affected by either IFN-gamma or IL-4, the binding of the factor to AU-rich sequences appeared to be important in the rapid degradation of TNF-alpha messages. Thus IFN-gamma and IL-4 may differentially affect the post-transcriptional control of TNF-alpha gene expression. And this lymphokine-mediated post-transcriptional control of the TNF-alpha gene does not appear to involve the alteration of binding activity of the 18,000 MW AU-rich sequence binding factor. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6

Suk, K; Erickson, K L

1996-01-01

282

Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder  

Microsoft Academic Search

RationaleOver the last 15 years, an increasing body of evidence has suggested a causal relationship between depression and the immunological activation and hypersecretion of pro-inflammatory cytokines, such as interleukin-1, interleukin-6 and tumor necrosis factor-alpha (TNF-a). However, little is known about the probable relationship of serum TNF-a with major depressive disorder (MDD).ObjectiveTo assess whether serum TNF-a levels could be associated with

Cengiz Tuglu; S. Hakan Kara; Okan Caliyurt; Erdal Vardar; Ercan Abay

2003-01-01

283

Tumor necrosis factor-alpha ?G308A polymorphism in schizophrenia in a Finnish population  

Microsoft Academic Search

Tumor necrosis factor-alpha (TNF-?) is a proinflammatory cytokine with functions in nerve cell growth, differentiation, and apoptosis. There are several studies showing that a TNF-? ?G308A promoter polymorphism, which possibly affects TNF-? transcription, is associated with schizophrenia, although negative results also exist. Our aim was to investigate the relationship between the TNF-? ?G308A promoter polymorphism, the risk of schizophrenia, and

Kari Hänninen; Heikki Katila; Riikka Rontu; Kari M. Mattila; Mikko Hurme; Terho Lehtimäki

2005-01-01

284

Measurement of synovial tumor necrosis factor-alpha in diagnosing emergency patients with bacterial arthritis  

Microsoft Academic Search

Because of the high morbidity and mortality in patients with bacterial arthritis, rapidly and correctly diagnosing this critical condition is a challenge to emergency clinicians. Synovial fluid samples were obtained from 75 patients with arthritis disorders who presented to an emergency service, and levels of tumor necrosis factor-alpha (TNF-?), interleukin-1 beta (IL-1?), and interleukin-6 (IL-6) were measured. Twenty patients with

Geng-Wang Jeng; Chrong-Reen Wang; Shyh-Tsair Liu; Che-Chun Su; Rong-Tai Tsai; Tsann-Sheng Yeh; Chia-Lin Wen; Yea-Quey Wu; Chang-Yu Lin; Gwon-Loon Lee; Mao-Yuan Chen; Ming-Fei Liu; Che-Yen Chuang; Cheng-Yen Chen

1997-01-01

285

INTERLEUKIN6 AND TUMOR NECROSIS FACTOR-ALPHA VALUES IN ELK NEONATES  

Microsoft Academic Search

Serological indicators of general condition would be helpful for monitoring or assessing ungulate wildlife. Toward that end, we report the 1st reference values for 2 cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a), in neonatal elk (Cervus elaphus). We obtained blood samples from 140 calves ? 6 days old in Yellowstone National Park during summer 2003-2005. IL-6 values ranged from

Shannon M. Barber-Meyer; Craig R. Johnson; Michael P. Murtaugh; L. David Mech; P. J. White

2007-01-01

286

Anomalous Role of Tumor Necrosis Factor Alpha in Experimental Enterococcal Infection  

Microsoft Academic Search

The murine D-galactosamine (D-gal) model of tumor necrosis factor alpha (TNF-) hypersensitization was used as an initial tool to investigate the potential contribution of TNF- to lethal intraperitoneal (i.p.) infection with Enterococcus faecalis. D-gal sensitized mice to lethal E. faecalis infection, whereas dexamethasone and neutralizing anti-TNF- antibody protected D-gal-treated, E. faecalis-infected mice, implicating TNF- in the lethal response to E.

Christopher J. Papasian; Richard Silverstein; Jian Jun Gao; David M. Bamberger; David C. Morrison

2002-01-01

287

A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells  

Microsoft Academic Search

Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins1. Modification of the cell surface in this way can alter the cell's responsiveness to its environment2 and release potent soluble regulatory factors3. The release of soluble tumour-necrosis factor-alpha (TNF-alpha) from its membrane-bound precursor4,5 is one of the most intensively studied shedding events because this inflammatory cytokine is so

Roy A. Black; Charles T. Rauch; Carl J. Kozlosky; Jacques J. Peschon; Jennifer L. Slack; Martin F. Wolfson; Beverly J. Castner; Kim L. Stocking; Pranitha Reddy; Subhashini Srinivasan; Nicole Nelson; Norman Boiani; Kenneth A. Schooley; Mary Gerhart; Raymond Davis; Jeffrey N. Fitzner; Richard S. Johnson; Raymond J. Paxton; Carl J. March; Douglas Pat Cerretti

1997-01-01

288

Rapid genotyping of tumor necrosis factor alpha with fluorogenic hybridization probes on the LightCycler™  

Microsoft Academic Search

Genotyping of tumor necrosis factor alpha (TNF-?) has become an important procedure in the selection of high-risk population\\u000a of septic shock and prevention from death due to septic shock. We present a single-tube method for TNF-? genotyping that performed\\u000a on the LightCycler by melting curve analysis with allele-specific fluorescent probe. A fragment covering the polymorphic site\\u000a is amplified in the

Naoko Hayashi; Yu Imamura; Yukiharu Hiyoshi; Hiroshi Takamori; Toru Beppu; Masahiko Hirota; Hideo Baba

2008-01-01

289

Tumor necrosis factor-alpha as a potential therapeutic target in idiopathic inflammatory myopathies  

Microsoft Academic Search

The cytokine, tumor necrosis factor alpha (TNF?), has been implicated in many aspects of immune system development, immune\\u000a response regulation, and T cell-mediated tissue injury. TNF? plays a less well-defined role in the pathogenesis of the idiopathic\\u000a inflammatory myopathy (IIM) group of disorders, and has been considered a potential therapeutic target. Observational studies\\u000a of TNF?-blockade in (mostly refractory) IIM have

Joerg-Patrick Stübgen

2011-01-01

290

[Treatment of fistulating pouchitis with tumour necrosis factor-alpha-inhibitor (infliximab)].  

PubMed

The surgical first choice treatment for patients with ulcerative colitis (UC) involves total proctocolectomy with ileal pouch-anal anastomosis (IPAA). Postoperative development of pouch-related fistula is a rare complication, but it is associated with significant morbidity, a high recurrence rate and is a major cause of pouch failure. We report the use of infliximab, a monoclonal antibody to tumour necrosis factor-alpha, in three patients who developed pouch-related fistula after undergoing IPAA surgery for UC. PMID:19091194

Semb, Synne; Nordgaard-Lassen, Inge

2008-12-01

291

Lactobacilli and Streptococci Induce Interleukin12 (IL12), IL18, and Gamma Interferon Production in Human Peripheral Blood Mononuclear Cells  

Microsoft Academic Search

Human peripheral blood mononuclear cells (PBMC) were stimulated with three nonpathogenic Lactobacillus strains and with one pathogenic Streptococcus pyogenes strain, and cytokine gene expression and protein pro- duction were analyzed. All bacteria strongly induced interleukin-1b (IL-1b), IL-6, and tumor necrosis factor alpha mRNA expression and protein production. S. pyogenes was the most potent inducer of secretion of IL-12 and gamma

MINJA MIETTINEN; SAMPSA MATIKAINEN; JAANA VUOPIO-VARKILA; JAANA PIRHONEN; KARI VARKILA; MASASHI KURIMOTO; ILKKA JULKUNEN; Orion Pharma

1998-01-01

292

Alpha-quartz-induced chemokine expression by rat lung epithelial cells: effects of in vivo and in vitro particle exposure.  

PubMed Central

Chemokines are chemotactic cytokines that can play a key role in leukocyte recruitment to sites of tissue injury or infection. Previous studies have demonstrated that exposure to alpha-quartz as well as other noxious particles increases chemokine gene expression in rat lung, although the cells responsible for chemokine expression and the mechanisms underlying this response have remained unclear. The present studies demonstrate that exposure of rats to alpha-quartz induced expression of mRNA for the chemokine macrophage-inflammatory protein (MIP)-2 in epithelial cells lining the terminal bronchioles and alveolar ducts as well as macrophages and alveolar type II cells in the more distal lung. Treatment of rats with an anti-MIP-2 antiserum before alpha-quartz exposure markedly attenuated neutrophilic infiltration of the lungs demonstrating an important role for MIP-2 in alpha-quartz-induced pulmonary inflammation. In vitro exposure of primary cultures of rat alveolar type II cells or the rat alveolar type II cell line RLE-6TN to tumor necrosis factor-alpha, endotoxin, or alpha-quartz increased mRNA for MIP-2 as well as the structurally and functionally similar chemokine cytokine-induced neutrophil chemoattractant but not the chemokine MIP-1 alpha. The alpha-quartz-induced increase in epithelial MIP-2 mRNA resulted, at least in part, from increased gene transcription and was associated with the release of active MIP-2 protein. Induction of RLE-6TN MIP-2 and cytokine-induced neutrophil chemoattractant mRNA expression was not unique to alpha-quartz, being also increased by crocidolite asbestus fibers but not by titanium dioxide or MMVF-10 glass fibers. These findings indicate that epithelial cells contribute to chemokine expression in rat lung after exposure to alpha-quartz and potentially other noxious particles and suggest that alpha-quartz-activated MIP-2 expression in vivo results, at least in part, from a direct action of the particles on the lung epithelium. Images Figure 1 Figure 3 Figure 5 Figure 6 Figure 7 Figure 8

Driscoll, K. E.; Howard, B. W.; Carter, J. M.; Asquith, T.; Johnston, C.; Detilleux, P.; Kunkel, S. L.; Isfort, R. J.

1996-01-01

293

Sleep deprivation attenuates endotoxin-induced cytokine gene expression independent of day length and circulating cortisol in male Siberian hamsters (Phodopus sungorus).  

PubMed

Sleep is restorative, whereas reduced sleep leads to negative health outcomes, such as increased susceptibility to disease. Sleep deprivation tends to attenuate inflammatory responses triggered by infection or exposure to endotoxin, such as bacterial lipopolysaccharide (LPS). Previous studies have demonstrated that Siberian hamsters (Phodopus sungorus), photoperiodic rodents, attenuate LPS-induced fever, sickness behavior and upstream pro-inflammatory gene expression when adapted to short day lengths. Here, we tested whether manipulation of photoperiod alters the suppressive effects of sleep deprivation upon cytokine gene expression after LPS challenge. Male Siberian hamsters were adapted to long (16 h:8 h light:dark) or short (8 h:16 h light:dark) photoperiods for >10 weeks, and were deprived of sleep for 24 h using the multiple platform method or remained in their home cage. Hamsters received an intraperitoneal injection of LPS or saline (control) 18 h after starting the protocol, and were killed 6 h later. LPS increased liver and hypothalamic interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) gene expression compared with vehicle. Among LPS-challenged hamsters, sleep deprivation reduced IL-1 mRNA levels in liver and hypothalamus, but not TNF. IL-1 attenuation was independent of circulating baseline cortisol, which did not increase after sleep deprivation. Conversely, photoperiod altered baseline cortisol, but not pro-inflammatory gene expression in sleep-deprived hamsters. These results suggest that neither photoperiod nor glucocorticoids influence the suppressive effect of sleep deprivation upon LPS-induced inflammation. PMID:23531821

Ashley, Noah T; Walton, James C; Haim, Achikam; Zhang, Ning; Prince, Laura A; Fruchey, Allison M; Lieberman, Rebecca A; Weil, Zachary M; Magalang, Ulysses J; Nelson, Randy J

2013-03-26

294

Production of tumor necrosis factors alpha and beta by human mononuclear leukocytes stimulated with mitogens, bacteria, and malarial parasites.  

PubMed Central

Tumor necrosis factors alpha and beta (TNF-alpha and TNF-beta) are multifaceted polypeptide cytokines which may mediate some of the significant changes in cellular homeostasis which accompany the invasion of the mammalian host by viruses, bacteria, and parasites. Although it is well established that bacterial lipopolysaccharide is a potent inducer of TNF-alpha, there is still very little known of the types of agents which can trigger the production of TNFs in mononuclear leukocytes. Using an enzyme-linked immunosorbent assay for measuring TNF-alpha and TNF-beta, we examined the capacity of various T-lymphocyte and beta-lymphocyte mitogens as well as microbial components to stimulate production of these cytokines in culture. The mitogens phytohemagglutinin, concanavalin A, and pokeweed mitogen induced production of both TNF-alpha and TNF-beta, while whole-killed Staphylococcus aureus and Bordetella pertussis, like lipopolysaccharide, were potent inducers of TNF-alpha but failed to stimulate TNF-beta production. TNF-alpha production was detectable within 1 h after stimulation, while TNF-beta production was not detected until after 8 h of culture. The bacterial products tetanus toxoid, purified protein derivative, pertussis filamentous hemagglutinin, and pertussis toxin were all able to induce TNF-alpha and TNF-beta production. Disrupted (frozen-thawed) Plasmodium falciparum-infected erythrocytes were also potent inducers of TNF-alpha and TNF-beta. The results demonstrated that a wide variety of microbial components are inducers of TNF-alpha. Some may not only be more effective than lipopolysaccharide but can also induce TNF-beta production. Furthermore, evidence is presented showing that TNF-beta but not TNF-alpha production correlates with lymphoproliferation.

Ferrante, A; Staugas, R E; Rowan-Kelly, B; Bresatz, S; Kumaratilake, L M; Rzepczyk, C M; Adolf, G R

1990-01-01

295

Histamine Induces Tissue Factor Expression Implications for Acute Coronary Syndromes  

Microsoft Academic Search

Background—Histamine can induce coronary vasospasm, leading to variant angina and acute myocardial infarction. However, the role of histamine in thrombus formation is ill defined. Hence, this study investigates whether histamine induces tissue factor (TF) expression in vascular cells. Methods and Results—Histamine (108 to 105 mol\\/L) induced TF expression in a concentration-dependent manner in human aortic endothelial and vascular smooth muscle

Jan Steffel; Alexander Akhmedov; Helen Greutert; Thomas F. Lüscher; Felix C. Tanner

296

Molecular cloning and characterization of beluga whale (Delphinapterus leucas) interleukin-1beta and tumor necrosis factor-alpha.  

PubMed Central

Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are cytokines produced primarily by monocytes and macrophages with regulatory effects in inflammation and multiple aspects of the immune response. As yet, no molecular data have been reported for IL-1beta and TNF-alpha of the beluga whale. In this study, we cloned and determined the entire cDNA sequence encoding beluga whale IL-1beta and TNF-alpha. The genetic relationship of the cytokine sequences was then analyzed with those from several mammalian species, including the human and the pig. The homology of beluga whale IL-1beta nucleic acid and deduced amino acid sequences with those from these mammalian species ranged from 74.6 to 86.0% and 62.7 to 77.1%, respectively, whereas that of TNF-alpha varied from 79.3 to 90.8% and 75.3 to 87.7%, respectively. Phylogenetic analyses based on deduced amino acid sequences showed that the beluga whale IL-1beta and TNF-alpha were most closely related to those of the ruminant species (cattle, sheep, and deer). The beluga whale IL-1beta- and TNF-alpha-encoding sequences were thereafter successfully expressed in Escherichia coli as fusion proteins by using procaryotic expression vectors. The fusion proteins were used to produce beluga whale IL-1beta- and TNF-alpha-specific rabbit antisera. Images Figure 3. Figure 4. Figure 5.

Denis, F; Archambault, D

2001-01-01

297

Influence of Tumour Necrosis Factor Alpha on the Outcome of Ischaemic Postconditioning in the Presence of Obesity and Diabetes  

PubMed Central

Obesity and diabetes contribute to cardiovascular disease and alter cytokine profile. The cytokine, tumour necrosis factor alpha (TNF?), activates a protective signalling cascade during ischaemic postconditioning (IPostC). However, most successful clinical studies with IPostC have not included obese and/or diabetic patients. We aimed to investigate the influence of TNF? on the outcome of IPostC in obese or diabetic mice. TNF knockout or wildtype mice were fed for 11 weeks with a high carbohydrate diet (HCD) to induce modest obesity. Diabetes was induced in a separate group by administration of a single intraperitoneal injection of streptozotocin. Hearts were then isolated and subjected to ischaemia (35?min of global ischaemia) followed by 45?min of reperfusion. HCD increased body weight, plasma insulin and leptin levels while the glucose level was unchanged. In streptozotocin-treated mice, blood glucose, plasma leptin and insulin were altered. Control, obese or diabetic mice were protected with IPostC in wiltype animals. In TNF knockout mice, IPostC failed to protect control and diabetic hearts while a slight protection was observed in obese hearts. Our data confirm a bidirectional role for TNF? associated with the severity of concomitant comorbidities and suggest that diabetic and/or modestly obese patients may still benefit from IPostC.

Lacerda, Lydia; Opie, Lionel H.; Lecour, Sandrine

2012-01-01

298

Interleukin-1beta and tumour necrosis factor-alpha promote the transformation of human immortalised mesothelial cells by erionite.  

PubMed

Asbestos fails to induce the transformation of human mesothelial cells in vitro although it has been known as a potential carcinogen to human mesothelial cells. Interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) are major cytokines released by macrophages after inhalation of asbestos. These cytokines can regulate mesothelial cell proliferation both in vitro and in vivo. In the present study, we used the growth in soft agar as an index of transformation and investigated the role of IL-1beta and TNF-alpha during the process of human mesothelial cell carcinogenesis. Both IL-1beta and TNF-alpha were demonstrated to enhance erionite-induced transformation of the immortalised, non-tumorigenic human mesothelial cell line (MeT-5A) in vitro. The MeT-5A cells could only be transformed when the cells were exposed to a combination of cytokines and erionite, or at least two cytokines together without erionite, for at least 4 months in vitro. The findings presented here suggest that IL-1beta and TNF-alpha play a significant role in the pathogenesis of mesothelioma, and that it might be desirable to block or inhibit cytokine secretion in high risk populations to prevent mesothelioma. PMID:15202003

Wang, Yaohe; Faux, Steven P; Hallden, Gunnel; Kirn, David H; Houghton, Cathy E; Lemoine, Nicholas R; Patrick, Graham

2004-07-01

299

Inducible Gene Expression in Mammals: Plants Add to the Menu  

NSDL National Science Digital Library

Achieving inducible gene expression in mammalian cells with inexpensive and nontoxic inducers is an ongoing quest. The plant hormone abscisic acid has now been added to the list of compounds that can be used for regulating transcription and controlling protein function by induced proximity. These advances may enable new clinical applications of proximity-induced systems, and they highlight the value of fundamental research in plant biology.

Sean R. Cutler (Department of Botany and Plant Sciences;Center for Plant Cell Biology REV)

2011-03-15

300

Inhibition of tumor necrosis factor-alpha production by SK&F 98625, a CoA-independent transacylase inhibitor, in cultured rat peritoneal macrophages.  

PubMed

When rat peritoneal macrophages were incubated in medium containing thapsigargin, tumor necrosis factor-alpha (TNF-alpha) production was increased time-dependently. In the presence of SK&F 98625, a CoA-independent transacylase inhibitor, the thapsigargin-induced TNF-alpha production was inhibited dose-dependently. Platelet-activating factor (PAF) and prostaglandin E2 (PGE2) production were also inhibited by SK&F 98625. The SK&F 98625-induced inhibition of TNF-alpha production was not prevented by addition of PGE2. PAF antagonists such as E6123, L-652,731 and CV-6209 partially inhibited the thapsigargin-induced TNF-alpha production, suggesting that concurrently produced PAF in thapsigargin-stimulated macrophages up-regulates TNF-alpha production. The inhibition by SK&F 98625 of thapsigargin-induced TNF-alpha production might be partly due to the inhibition of PAF production. PMID:9600332

Yamada, M; Ichinowatari, G; Tanimoto, A; Yaginuma, H; Ohuchi, K

1998-01-01

301

Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in Type 2 diabetics and patients with android type obesity.  

PubMed

The role of tumor necrosis factor-alpha in insulin resistance has been studied in 59 patients with Type 2 diabetes, 28 with android type obesity and 35 healthy lean controls. Immunoreactive concentrations and bioactivity of serum tumor necrosis factor-alpha have repeatedly been determined in 8 weeks intervals for 12 months, five times per patients, by using ELISA and L929 cell cytotoxicity bioassay. Significantly higher immunoreactive tumor necrosis factor-alpha concentrations and bioactivity have been found in both, the Type 2 diabetic and obese groups as compared to the healthy persons. Tumor necrosis factor-alpha concentrations and bioactivity have showed a significant positive linear correlation with the elevated basal serum C-peptide levels and body mass indexes in both groups of patients. According to these data the cytokine might play a role in insulin resistance in obesity as well in Type 2 diabetes. PMID:9925347

Winkler, G; Salamon, F; Harmos, G; Salamon, D; Speer, G; Szekeres, O; Hajós, P; Kovács, M; Simon, K; Cseh, K

1998-12-01

302

Tumor necrosis factor-alpha promotes survival in methotrexate-exposed macrophages by an NF-kappaB-dependent pathway  

PubMed Central

Introduction Methotrexate (MTX) induces macrophage apoptosis in vitro, but there is not much evidence for increased synovial macrophage apoptosis in MTX-treated patients. Macrophage apoptosis is reported, however, during clinical response to anti-tumor necrosis factor-alpha (TNF-?) treatments. This implies that TNF-? promotes macrophage survival and suggests that TNF-? may protect against MTX-induced apoptosis. We, therefore, investigated this proposal and the macrophage signaling pathways underlying it. Methods Caspase-3 activity, annexin-V binding/7-aminoactinomycin D (7-AAD) exclusion and cell-cycle analysis were used to measure steps in apoptosis of primary murine macrophages and cells of the RAW264.7 macrophage cell line that had been exposed to clinically-relevant concentrations of MTX and TNF-?. Results MTX induces apoptosis in primary murine macrophages at concentrations as low as 100 nM in vitro. TNF-?, which has a context-dependent ability to increase or to suppress apoptosis, efficiently suppresses MTX-induced macrophage apoptosis. This depends on NF-?B signaling, initiated through TNF Receptor Type 1 ligation. Macrophage colony stimulating factor, the primary macrophage survival and differentiation factor, does not activate NF-?B or protect macrophages from MTX-induced apoptosis. A weak NF-?B activator, Receptor Activator of NF-?B Ligand (RANKL) is likewise ineffective. Blocking NF-?B in TNF-?-exposed macrophages allowed pro-apoptotic actions of TNF-? to dominate, even in the absence of MTX. MTX itself does not promote apoptosis through interference with NF-?B signaling. Conclusions These findings provide another mechanism by which TNF-? sustains macrophage numbers in inflamed tissue and identify a further point of clinical complementarity between MTX and anti-TNF-? treatments for rheumatoid arthritis.

2011-01-01

303

Inducible gene expression: diverse regulatory mechanisms  

Microsoft Academic Search

The rapid activation of gene expression in response to stimuli occurs largely through the regulation of RNA polymerase II-dependent transcription. In this Review, we discuss events that occur during the transcription cycle in eukaryotes that are important for the rapid and specific activation of gene expression in response to external stimuli. In addition to regulated recruitment of the transcription machinery

Vikki M. Weake; Jerry L. Workman

2010-01-01

304

Inducible gene expression systems and plant biotechnology  

Microsoft Academic Search

Plant biotechnology relies heavily on the genetic manipulation of crops. Almost invariantly, the gene of interest is expressed in a constitutive fashion, although this may not be strictly necessary for several applications. Currently, there are several regulatable expression systems for the temporal, spatial and quantitative control of transgene activity. These molecular switches are based on components derived from different organisms,

Giandomenico Corrado; Marianthi Karali

2009-01-01

305

Tumor necrosis factor-alpha participates in apoptosis in the limbic system after myocardial infarction  

Microsoft Academic Search

This study was designed to determine the role of tumor necrosis factor-alpha (TNF?) in apoptosis observed in the myocardium\\u000a and limbic system after myocardial ischemia. PEG sTNFRI, a recombinant, human, soluble p55 Type 1 TNF receptor (3 mg\\/kg) or\\u000a vehicle (saline) was administered s.c. to male Sprague-Dawley rats on days 5, 3 and 1 before myocardial ischemia. The animals\\u000a were then

S. Kaloustian; T. M. Bah; I. Rondeau; S. Mathieu; L. Lada-Moldovan; P. Ryvlin; R. Godbout; G. Rousseau

2009-01-01

306

Increased tumor necrosis factor. alpha. mRNA after cellular exposure to ionizing radiation  

SciTech Connect

The authors report that tumor necrosis factor {alpha} (TNF-{alpha}) mRNA is increased after treatment with x-rays in certain human sarcoma cells. An increase in TNF-{alpha} mRNA is accompanied by the increased production of TNF-{alpha} protein. TNF-{alpha} enhances radiation lethality in both TNF-{alpha}-producing and -nonproducing tumor cells. These data suggest that, in addition to the direct cytotoxic effects of x-rays, production of TNF-{alpha} may add to radiation lethality through autocrine and paracrine mechanisms. Combinations of TNF-{alpha} and therapeutic radiation may be useful in clinical therapy.

Hallahan, D.E.; Beckett, M.A.; Weichselbaum, R.R. (Univ. of Chicago, IL (USA)); Spriggs, D.R. (Dana-Farber Cancer Institute, Boston, MA (USA))

1989-12-01

307

N-Formyl-Methionyl-Leucyl-Phenylalanine Inhibits both Gamma Interferon- and Interleukin-10-Induced Expression of Fc?RI on Human Monocytes  

PubMed Central

Three different classes of receptors for the Fc portion of immunoglobulin G (Fc?Rs), Fc?RI, Fc?RII, and Fc?RIII, have been identified on human leukocytes. One of them, Fc?RI, is a high-affinity receptor capable of induction of functions that include phagocytosis, respiratory burst, antibody-dependent cell-mediated cytotoxicity (ADCC), and secretion of cytokines. This receptor is expressed on mononuclear phagocytes, and this expression is regulated by cytokines and hormones such as gamma interferon (IFN-?), IFN-?, interleukin-10 (IL-10), and glucocorticoids. We have recently demonstrated that the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is capable of inducing a time-dependent downregulation of both Fc?RIIIB and Fc?RII in human neutrophils, altering Fc?R-dependent functions. Considering the biological relevance of the regulation of Fc?RI, we investigated the effect of FMLP on the overexpression of Fc?RI induced by both IFN-? and IL-10 on human monocytes. We demonstrate that FMLP significantly abrogated IFN-?- and IL-10-induced Fc?RI expression, although its basal level of expression was not altered. However, other IFN-?-mediated effects such as the overexpression of the major histocompatibility complex class II antigens and the enhancement of lipopolysaccharide-induced secretion of tumor necrosis factor alpha were not affected by FMLP treatment. The formyl peptide completely inhibited the IFN-?- and IL-10-induced enhancement of ADCC and phagocytosis carried out by adherent cells. The inhibitory effect of FMLP on Fc?RI upregulation could exert an important regulatory effect during the evolution of bacterial infections.

Beigier-Bompadre, Macarena; Barrionuevo, Paula; Alves-Rosa, Fernanda; Rubel, Carolina J.; Palermo, Marina S.; Isturiz, Martin A.

2001-01-01

308

Increased mesangial cell hyaluronan expression in lupus nephritis is mediated by anti-DNA antibody-induced IL-1beta.  

PubMed

The mechanism by which anti-DNA antibodies contribute to the pathogenesis of lupus nephritis (LN) remains to be fully elucidated. Hyaluronan (HA) is an important extracellular matrix constituent that accumulates during tissue injury, and participates in lymphocyte recruitment to sites of inflammation. The role of HA in the pathogenesis of LN has not been defined. We investigated the expression of HA in renal biopsies and circulating HA levels in patients with diffuse proliferative LN, and the effect of human anti-DNA antibodies on HA synthesis in cultured human mesangial cells (HMC). HA expression was increased in the mesangium, and in the periglomerular and tubular distribution in LN kidney biopsies. LN patients showed increased levels of circulating HA, especially during active disease, which correlated with anti-DNA antibody titers (r=0.35, P=0.0234). Anti-DNA antibodies isolated during active LN but not remission increased de novo synthesis of (3)H-labeled HA, which was accompanied by induction of HA synthase (HAS) II transcription, and enhanced IL-1beta, IL-6, and tumor necrosis factor-alpha secretion in HMC (P<0.001 for all). Only anti-DNA antibody induction of IL-1beta enhanced HA synthesis, which was abrogated by inhibitors of de novo mRNA or protein synthesis. Our findings demonstrate that HA expression is significantly increased within the mesangium in diffuse proliferative LN mediated through anti-DNA antibody-induced IL-1beta. Given that HA plays a pivotal role during inflammatory responses, influences cellular behavior and assists in the recruitment of lymphocytes to sites of injury, it is likely that HA contributes to the pathogenesis of LN. PMID:16408116

Yung, S; Tsang, R C W; Leung, J K H; Chan, T M

2006-01-01

309

FRAP DNA-dependent protein kinase mediates a late signal transduced from ultraviolet-induced DNA damage.  

PubMed

Ultraviolet radiation induces signal transduction at both early (<6 h) and late (>6 h) times after exposure. The inflammatory and immunosuppressive cytokine tumor necrosis factor alpha is induced at late times, and is induced by ultraviolet-induced DNA damage, as defects in DNA repair increase, and enhanced photoproduct repair reduces, tumor necrosis factor alpha expression. Here we show that late tumor necrosis factor alpha gene expression is sensitive to rapamycin, implicating FKBP12-rapamycin-associated protein, a member of the DNA protein kinase family, as a signal transducer of ultraviolet-induced DNA damage. FKBP12-rapamycin-associated protein was localized in the nucleus of keratinocytes and its level was increased following ultraviolet irradiation. Immuno- precipitated FKBP12-rapamycin-associated protein was stimulated by ultraviolet-irradiated DNA to phosphorylate p53 in vitro, and in vivo rapamycin reduced ultraviolet induction of p53 by 20%. Rapamycin further inhibited the ultraviolet-induced phosphorylation of the FKBP12-rapamycin-associated protein downstream target kinase p70S6K. In mice, topical application of rapamycin before ultraviolet exposure protected against suppression of the contact hypersensitivity that is a hallmark of ultraviolet-induced cytokine gene expression. These results demonstrate that the FKBP12-rapamycin-associated DNA protein kinase transduces the signal of ultraviolet-induced DNA damage into production of immunosuppressive cytokines at late times after ultraviolet irradiation. PMID:10771484

Yarosh, D B; Cruz, P D; Dougherty, I; Bizios, N; Kibitel, J; Goodtzova, K; Both, D; Goldfarb, S; Green, B; Brown, D

2000-05-01

310

Molecular design of hybrid tumour necrosis factor alpha with polyethylene glycol increases its anti-tumour potency.  

PubMed Central

This study was conducted to increase the anti-tumour potency and reduce the toxic side-effects of tumour necrosis factor alpha (TNF-alpha). Natural human TNF-alpha was chemically conjugated with monomethoxy polyethylene glycol (PEG) using succinimidyl coupling of lysine amino groups of TNF-alpha. The number-average molecular weight of PEG-modified TNF-alpha (PEG-TNF-alpha) increased with an increase in the reaction time and the initial molar ratio of PEG relative to TNF-alpha. The resulting modified TNF-alpha was separated into fractions of various molecular weights. The specific activity of separated PEG-TNF-alpha s relative to that of native TNF-alpha gradually decreased with an increase in the degree of PEG modification, but the plasma half-life was drastically increased with the increase in molecular weight of modified TNF-alpha. PEG-TNF-alpha s, in which 29% and 56% of lysine residues were coupled to PEG, had anti-tumour activity approximately 4 and 100 times greater than unmodified TNF-alpha in the murine Meth-A fibrosarcoma model. Extensive PEG modification did not increase its in vivo activity. A high dose of unmodified TNF-alpha induced toxic side-effects, but these were not observed with the modified TNF-alpha s. Optimal PEG modification of TNF-alpha markedly increased its bioavailability and may facilitate its potential anti-tumour therapeutic use.

Tsutsumi, Y.; Kihira, T.; Tsunoda, S.; Kanamori, T.; Nakagawa, S.; Mayumi, T.

1995-01-01

311

Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice.  

PubMed

Painful diabetic neuropathy is one of the most common forms of neuropathic pain syndromes. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated as a key pain mediator in the development and maintenance of neuropathic pain conditions. Recent studies showed that endogenous TNF-alpha production was also accelerated in neural tissues and spinal cord under chronic hyperglycemia. Thus, in this study, we investigated whether pharmacological inhibition of TNF-alpha by etanercept, a TNF-alpha antagonist, could block behavioral sign of diabetic neuropathic pain. Diabetes was induced by streptozotocin (STZ) (200 mg/kg, i.p.) in Balb-c mice and behavioral tests were performed between 45 and 60 days after STZ administration. Mechanical and thermal sensitivities were measured by a series of calibrated Von Frey filaments and hot plate test, respectively. Etanercept was given by either intravenous (i.v.), intrathecal (i.th.) or intraplantar (i.pl.) routes to the diabetic mice. Tactile allodynia, but not thermal hyperalgesia, developed in diabetic mice. Both i.v. (1, 10 and 20 mg/kg) or i.th. (1, 5 and 10 ?g/mouse) treatments with etanercept produced dose dependent reversal of tactile allodynia in diabetic mice. However, etanercept was found to be inactive against allodynia when given i.pl. (1, 5 and 10 ?g/mouse). Our results suggest that etanercept has promising effects on diabetic neuropathic pain with antiallodynic effects when given systemically or intrathecally. PMID:21104419

Dogrul, Ahmet; Gul, Husamettin; Yesilyurt, Ozgur; Ulas, Umit H; Yildiz, Oguzhan

2010-11-23

312

Activation of hepatic branched-chain alpha-keto acid dehydrogenase complex by tumor necrosis factor-alpha in rats.  

PubMed

Tumor necrosis factor-alpha (TNFalpha) promotes oxidation of branched-chain amino acids (BCAA). BCAA catabolism is regulated by branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which is regulated by phosphorylation-dephosphorylation of the E1alpha subunit at Ser293. BCKDH kinase is responsible for inactivation of the complex by phosphorylation. In the present study, we examined the effects of TNFalpha administration on hepatic BCKDH complex and kinase in rats. Rats were intravenously administered with 25 or 50 microg TNFalpha/kg body weight 4 h prior to sacrifice. The TNFalpha treatment at both doses elevated the activity state (percentage of the active form) of BCKDH complex from 22% to 69% and 86%, respectively, and the amount of phospho-Ser293 on the E1alpha subunit in each group of rats corresponded inversely to the activity state of BCKDH complex. The TNFalpha treatment of rats significantly decreased the activity as well as the bound form of BCKDH kinase. These results suggest that the decrease in the bound form of kinase is involved in the mechanism responsible for TNFalpha-induced activation of the BCKDH complex. PMID:15707973

Shiraki, Makoto; Shimomura, Yoshiharu; Miwa, Yoshiyuki; Fukushima, Hideki; Murakami, Taro; Tamura, Tomohiro; Tamura, Noriko; Moriwaki, Hisataka

2005-03-25

313

Sensitive Immunoassay of a Biomarker Tumor Necrosis Factor-[alpha] Based on Poly(guanine)-Functionalized Silica Nanoparticle Label  

SciTech Connect

A novel electrochemical immunosensor for the detection of tumor necrosis factor-alpha (TNF-a) based on poly(guanine)-functionalized silica nanoparticles (NPs) label is presented. The detection of mouse TNF-a via immunological reaction is based on a dual amplification: 1) a large amount of guanine residues is introduced on the electrode surface through the silica nanoparticle and immunoreaction, 2) mediator-induced catalytic oxidation of guanine, which results in great enhancement of anodic current. The synthesized silica NP conjugates were characterized with atomic force microscopy, X-ray photoelectron spectroscopy, and electrochemistry. These experiments confirmed that poly[G] and avidin were immobilized on the surface of silica NPs. The performance of the electrochemical immunosensor was evaluated and some experiment parameters (e.g., concentration of Ru(bpy)32+, incubation time of TNF-a, etc.) were optimized. The detection of limit for TNF-a is found to be 5.0x10-11 g mL-1 (2.0 pM), which corresponds to 60 attomoles TNF-a in 30 uL. This immunosensor based on the poly[G] functionalized silica NP label offers great promise for rapid, simple, cost-effective analysis of biological samples.

Wang, Jun; Liu, Guodong; Engelhard, Mark H.; Lin, Yuehe

2006-10-01

314

Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart.  

PubMed Central

To define the mechanism(s) responsible for the negative inotropic effects of tumor necrosis factor-alpha (TNF alpha) in the adult heart, we examined the functional effects of TNF alpha in the intact left ventricle and the isolated adult cardiac myocyte. Studies in both the ventricle and the isolated adult cardiac myocyte showed that TNF alpha exerted a concentration- and time-dependent negative inotropic effect that was fully reversible upon removal of this cytokine. Further, treatment with a neutralizing anti-TNF alpha antibody prevented the negative inotropic effects of TNF alpha in isolated myocytes. A cellular basis for the above findings was provided by studies which showed that treatment with TNF alpha resulted in decreased levels of peak intracellular calcium during the systolic contraction sequence; moreover, these findings did not appear to be secondary to alterations in the electrophysiological properties of the cardiac myocyte. Further studies showed that increased levels of nitric oxide, de novo protein synthesis, and metabolites of the arachidonic acid pathway were unlikely to be responsible for the TNF alpha-induced abnormalities in contractile function. Thus, these studies constitute the initial demonstration that the negative inotropic effects of TNF alpha are the direct result of alterations in intracellular calcium homeostasis in the adult cardiac myocyte. Images

Yokoyama, T; Vaca, L; Rossen, R D; Durante, W; Hazarika, P; Mann, D L

1993-01-01

315

Hantavirus Infection Induces the Expression of RANTES and IP-10 without Causing Increased Permeability in Human Lung Microvascular Endothelial Cells  

PubMed Central

Sin Nombre virus (SNV) and Hantaan virus (HTN) infect endothelial cells and are associated with different patterns of increased vascular permeability during human disease. It is thought that such patterns of increased vascular permeability are a consequence of endothelial activation and subsequent dysfunction mediated by differential immune responses to hantavirus infection. In this study, the ability of hantavirus to directly induce activation of human lung microvascular endothelial cells (HMVEC-Ls) was examined. No virus-specific modulation in the constitutive or cytokine-induced expression of cellular adhesion molecules (CD40, CD54, CD61, CD62E, CD62P, CD106, and major histocompatibility complex classes I and II) or in cytokines and chemokines (eotaxin, tumor necrosis factor alpha, interleukin 1? [IL-1?], IL-6, IL-8, MCP-1, MIP-1?, and MIP-1?) was detected at either the protein or message level in hantavirus-infected HMVEC-Ls. Furthermore, no virus-specific enhancement of paracellular or transcellular permeability or changes in the organization and distribution of endothelial intercellular junctional proteins was observed. However, infection with either HTN or SNV resulted in detectable levels of the chemokines RANTES and IP-10 (the 10-kDa interferon-inducible protein) in HMVEC-Ls within 72 h and was associated with nuclear translocation of interferon regulatory factor 3 (IRF-3) and IRF-7. Gamma interferon (IFN-?)-induced expression of RANTES and IP-10 could also be detected in uninfected HMVEC-Ls and was associated with nuclear translocation of IRF-1 and IRF-3. Treatment of hantavirus-infected HMVEC-Ls with IFN-? for 24 h resulted in a synergistic enhancement in the expression of both RANTES and IP-10 and was associated with nuclear translocation of IRF-1, IRF-3, IRF-7, and NF-?B p65. These results reveal a possible mechanism by which hantavirus infection and a TH1 immune response can cooperate to synergistically enhance chemokine expression by HMVEC-Ls and trigger immune-mediated increases in vascular permeability.

Sundstrom, J. Bruce; McMullan, Laura K.; Spiropoulou, Christina F.; Hooper, W. Craig; Ansari, Aftab A.; Peters, Clarence J.; Rollin, Pierre E.

2001-01-01

316

Eugenol reduces acute pain in mice by modulating the glutamatergic and tumor necrosis factor alpha (TNF-?) pathways.  

PubMed

Eugenol is utilized together with zinc oxide in odontological clinical for the cementation of temporary prostheses and the temporary restoration of teeth and cavities. This work explored the antinociceptive effects of the eugenol in different models of acute pain in mice and investigated its possible modulation of the inhibitory (opioid) and excitatory (glutamatergic and pro-inflammatory cytokines) pathways of nociceptive signaling. The administration of eugenol (3-300 mg/kg, p.o., 60 min or i.p., 30 min) inhibited 82 ± 10% and 90 ± 6% of the acetic acid-induced nociception, with ID50 values of 51.3 and 50.2 mg/kg, respectively. In the glutamate test, eugenol (0.3-100 mg/kg, i.p.) reduced the response behavior by 62 ± 5% with an ID50 of 5.6 mg/kg. In addition, the antinociceptive effect of eugenol (10 mg/kg, i.p.) in the glutamate test was prevented by the i.p. treatment for mice with naloxone. The pretreatment of mice with eugenol (10 mg/kg, i.p.) was able to inhibit the nociception induced by the intrathecal (i.t.) injection of glutamate (37 ± 9%), kainic (acid kainite) (41 ± 12%), ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (55 ± 5%), and substance P (SP) (39 ± 8%). Furthermore, eugenol (10 mg/kg, i.p.) also inhibited biting induced by tumor necrosis factor alpha (TNF-?, 65 ± 8%). These results extend our current knowledge of eugenol and confirm that it promotes significant antinociception against different mouse models of acute pain. The mechanism of action appears to involve the modulation of the opioid system and glutamatergic receptors (i.e., kainate and AMPA), and the inhibition of TNF-?. Thus, eugenol could represent an important compound in the treatment for acute pain. PMID:22775297

Dal Bó, Wladmir; Luiz, Ana Paula; Martins, Daniel F; Mazzardo-Martins, Leidiane; Santos, Adair R S

2012-07-08

317

Red ginseng saponin extract attenuates murine collagen-induced arthritis by reducing pro-inflammatory responses and matrix metalloproteinase-3 expression.  

PubMed

Ginseng, the root of Panax ginseng C. A. MEYER, has been used as a food product and medicinal ingredient. In this study, we assessed the anti-arthritic effects of red ginseng saponin extract (RGSE), including ginsenosides Rg3, Rk1 and Rg5 as major components, on a murine type II collagen (CII)-induced arthritis (CIA), which is a valid animal model of human arthritis. Oral administration of RGSE at 10 mg/kg reduced the clinical arthritis score and paw swelling in the CIA mice, and inhibited joint space narrowing and histological arthritis, illustrating the severity of synovial hyperplasia, inflammatory cell infiltration, pannus formation, and erosion of cartilage. RGSE inhibited the expression of matrix metalloproteinase-3 and nitrotyrosine formation, and recovered the expression of superoxide dismutase in the joints of the CIA mice. Orally administered RGSE also reduced the levels of serum tumor necrosis factor-alpha and interleukin-1beta in the CIA mice. CII- or lipopolysaccharide-stimulated cytokine production, in addition to CII-specific proliferation, was reduced in the spleen cells of the RGSE-treated CIA mice, as compared with those from vehicle-treated CIA mice. Furthermore, RGSE administration protected against CIA-induced oxidative tissue damage by restoring the increased malondialdehyde levels and the decreased glutathione levels and catalase activities almost to control levels. Therefore, RGSE may be a beneficial supplement which can improve human arthritis. PMID:20410593

Kim, Ki Rim; Chung, Tae Yong; Shin, Heungsop; Son, Sung Ho; Park, Kwang-Kyun; Choi, Jong-Hoon; Chung, Won-Yoon

2010-01-01

318

Activation and Mitogen-Activated Protein Kinase Regulation of Transcription Factors Ets and NF B in Mycobacterium-Infected Macrophages and Role of These Factors in Tumor Necrosis Factor Alpha and Nitric Oxide Synthase 2 Promoter Function  

Microsoft Academic Search

Previous studies have shown that primary murine macrophages infected with Mycobacterium avium produced lower levels of tumor necrosis factor alpha (TNF-) and inducible nitric oxide synthase 2 (NOS2) compared to cells infected with nonpathogenic Mycobacterium smegmatis. TNF- and NOS2 levels correlated with and were dependent on the activation of mitogen-activated protein kinases (MAPKs) p38 and extracellular signal- regulated kinase 1\\/2

Seong-Beom Lee; Jeffrey S. Schorey

2005-01-01

319

Effects of Estradiol on Lipopolysaccharide and Pam3Cys Stimulation of CCL20\\/Macrophage Inflammatory Protein 3 Alpha and Tumor Necrosis Factor Alpha Production by Uterine Epithelial Cells in Culture  

Microsoft Academic Search

We have previously demonstrated that rat uterine epithelial cells (UEC) produce CCL20\\/macrophage inflammatory protein 3 alpha (MIP3) and tumor necrosis factor alpha (TNF-) in response to live and heat-killed Escherichia coli and to the pathogen-associated molecular patterns (PAMP) lipopolysaccharide (LPS) and Pam3Cys. To determine whether estradiol (E2) modulates PAMP-induced CCL20\\/MIP3 and TNF- secretion, primary cultures of rat UEC were incubated

Mardi A. Crane-Godreau; Charles R. Wira

2005-01-01

320

Dexamethasone indirectly induces Ndrg2 expression in rat astrocytes.  

PubMed

N-myc downstream-regulated gene 2 (Ndrg2) has been associated with cell proliferation, differentiation, and apoptosis. Ndrg2 expression in the brain is induced by glucocorticoid treatment or chronic stress in vivo. It has been postulated that glucocorticoid-induced Ndrg2 expression in astrocytes is regulated by the glucocorticoid response element half-site (GRE1/2) upstream of the Ndrg2 transcription site. Here we examined the mechanisms of dexamethasone-induced Ndrg2 expression in rat astrocytes. Ndrg2 mRNA expression in primary astrocytes was significantly increased after 24 hr of exposure to dexamethasone in a concentration-dependent manner. Dexamethasone-induced Ndrg2 mRNA and protein expression was blocked by pretreatment with RU486, a glucocorticoid receptor antagonist. Moreover, dexamethasone-induced Ndrg2 mRNA expression was reduced by pretreatment with the protein synthesis inhibitor cycloheximide. The Ndrg2 reporter assay showed that deletion of a putative GRE1/2, located upstream of Ndrg2, did not affect induction by dexamethasone. A region between -755 and -701 bp from the transcription start site was shown to regulate induction by dexamethasone using promoter constructs progressively deleted from the 5' to 3' ends. This region contained the predicted transcription factor binding sites for early B-cell factor 1 (Ebf1), nuclear factor-?B (NF?B), and paired box gene 5 (Pax5). Mutation at the NF?B- or Pax5-binding site, but not the Ebf1 binding site, abolished dexamethasone-induced promoter activation. These results indicate that Ndrg2 expression was indirectly induced by dexamethasone at the DNA level, potentially by the binding of NF?B or Pax5 to the transcription factor binding sites, and GRE1/2 was not involved in this induction. PMID:21928335

Takahashi, Kou; Saitoh, Akiyoshi; Yamada, Misa; Iwai, Takashi; Inagaki, Masatoshi; Yamada, Mitsuhiko

2011-09-16

321

Cloning of the DNA-binding subunit of human nuclear factor. kappa. B: The level of its mRNA is strongly regulated by phorbol ester or tumor necrosis factor. alpha  

SciTech Connect

The DNA binding subunit of nuclear factor {kappa}B (NF-{kappa}B), a B-cell protein that interacts with the immunoglobulin {kappa} light-chain gene enhancer, has been purified from nuclei of human HL-60 cells stimulated with tumor necrosis factor {alpha} (TNF{alpha}), and internal peptide sequences were obtained. Overlapping cDNA clones were isolated and sequenced. The encoded open reading frame of about 105 kDa contained at its N-terminal half all six tryptic peptide sequences, suggesting that the 51-kDa NF-{kappa}B protein is processed from a 105-kDa precursor. An in vitro synthesized protein containing most of the N-terminal half of the open reading frame bound specifically to an NF-{kappa}B binding site. This region also showed high homology to a domain shared by the Drosophila dorsal gene and the avian and mammalian rel (proto)oncogene products. The level of the 3.8-kilobase mRNA was strongly increased after stimulation with TNF{alpha} or phorbol ester. Thus, both factors not only activate NF-{kappa}B protein, as described previously, but also induce expression of the gene encoding the DNA-binding subunit of NF-{kappa}B.

Meyer, R.; Hatada, E.N.; Bartsch, C.; Scheidereit, C. (Max-Planck-Inst. fuer Molekulare Genetik, Berlin-Dahlem (West Germany)); Hohmann, H.P.; Haiker, M.; Roethlisberger, U.; Lahm, H.W.; Schlaeger, E.J.; van Loon, A.P.G.M. (F. Hoffmann-La Roche Ltd., Basel (Switzerland))

1991-02-01

322

Sequential Analysis of Gene Expression after an Osteogenic Stimulus - c- fos Expression Is Induced in Osteocytes  

Microsoft Academic Search

We have recently developed an experimental model whereby mechanical stimulation induces osteogenesis in the caudal vertebrae of rats. We used this model to assess expression of genes induced by mechanical loading. Bulk preparations of mRNA extracted after loading did not-show >2-fold increases in expression of mRNA for matrix proteins or growth factors in Northern blotting analysis. c-jun was undetectable. However,

T. Inaoka; J. M. Lean; T. Bessho; J. W. M. Chow; A. Mackay; T. Kokubo; T. J. Chambers

1995-01-01

323

Induction of tumor necrosis factor alpha by the group- and type-specific polysaccharides from type III group B streptococci.  

PubMed Central

Previous studies suggested that circulating tumor necrosis factor alpha (TNF-alpha) may have a pathophysiologic role in experimental neonatal sepsis induced by group B streptococci (GBS). This study was undertaken to investigate the ability of the type III and group-specific polysaccharides of GBS to induce TNF-alpha production and TNF-alpha-dependent lethality in neonatal rats. The cytokine was detected in plasma samples by the L929 cytotoxicity assay. Intracardiac injections of either polysaccharide induced dose-dependent, transient elevations in plasma TNF-alpha levels that returned to baseline values after 5 h. The group-specific antigen induced significantly higher mean peak TNF-alpha levels than the type III antigen (125 +/- 47 versus 44 +/- 15 U/ml with 70 mg/kg of body weight). Glycogen (70 mg/kg), used as a negative control, did not induce TNF-alpha. The lipopolysaccharide-neutralizing agent polymyxin B did not decrease TNF-alpha levels induced by either polysaccharide, ruling out contamination with endotoxin as a possible cause of TNF-alpha induction. Fifty percent lethal doses of the type III and group-specific antigens given as intracardiac injections were 105 and 16 mg/kg, respectively. Salmonella endotoxin, used as a positive control, had a 50% lethal dose of 0.1 mg/kg. The lethal activities of GBS polysaccharides, as well as endotoxin, were completely prevented by pretreatment of neonatal rats with the respective specific antibodies or anti-murine TNF-alpha serum. To assess the relative importance of the type-specific substance in TNF-alpha induction by whole bacteria, two unrelated GBS transposon mutants devoid of only the type-specific capsular polysaccharide (COH1-13 and COH31-15) were employed. Each of the heat-killed unencapsulated mutants was able to produce plasma TNF-alpha level elevations or TNF-alpha-dependent lethality but was significantly less efficient in these activities than the corresponding encapsulated wild-type strain. These data suggest that the presence of type-specific material on GBS is not necessary for the stimulation of TNF-alpha production. Type III capsular polysaccharide, however, can significantly increase the ability of GBS to induce TNF-alpha. Further studies will be needed to assess the importance of TNF-alpha induction by the group- and type-specific antigens in the pathophysiology of GBS disease.

Mancuso, G; Tomasello, F; von Hunolstein, C; Orefici, G; Teti, G

1994-01-01

324

Suppression of Lefty expression in induced pluripotent cancer cells.  

PubMed

Cancer and stem cells share the ability to silence tumor suppressors. We focused on Lefty, which encodes one of the most abundant tumor suppressors in embryonic stem (ES) cells and is not expressed in somatic cancer cells. We found that transforming growth factor ? (TGF-?) induced demethylation of the Lefty B cytosine-phosphate-guanine (CpG) island and increased Lefty expression (10-200 times) in human pancreatic cancer cells and human liver cancer cells (PLC/PRF/5 and HLF). Expression of Cripto, another important factor in Nodal-Lefty signaling, was not increased after adding TGF-?. We generated reprogrammed cancer cells that revealed high expression of immature marker proteins, high proliferation, and the potential to express morphological patterns of ectoderm, mesoderm, and endoderm, suggesting that these cells may have cancer stem cell-like phenotypes. We investigated Lefty and found that reprogrammed human liver cancer cells (induced pluripotent cancer cells) displayed a much lower ability to express Lefty, although less Lefty B CpG methylation was also observed. We also found that a MEK inhibitor dramatically enhanced Lefty expression in human pancreatic cancers with mutated ras, whereas Lefty B CpG methylation was not decreased. These observations indicate that despite the demethylation of DNA strands in promoter regions of pluripotency-associated genes, including Lefty gene, Lefty expression was not induced well in reprogrammed cells. Of note was the fact that Lefty is abundantly expressed in human ES cells but not in induced pluripotent stem (iPS) cells. We thus think that reprogrammed cancer cells share the mechanism for expression of Lefty with iPS cells. This shared mechanism may contribute to the cancerous transformation of iPS cells. PMID:23407711

Saito, Akiko; Ochiai, Hiromi; Okada, Shoko; Miyata, Naoteru; Azuma, Toshifumi

2013-02-13

325

Streptococcal Histone Induces Murine Macrophages To Produce Interleukin1 and Tumor Necrosis Factor Alpha  

Microsoft Academic Search

The histone-like protein (HlpA) is highly conserved among streptococci. After lysis of streptococci in infected tissues, HlpA can enter the bloodstream and bind to proteoglycans in the glomerular capillaries of kidneys, where it can react with antibodies or stimulate host cell receptors. Deposits of streptococcal antigens in tissues have been associated with localized acute inflammation. In this study, we measured

LIPING ZHANG; TRACEY A. IGNATOWSKI; ROBERT N. SPENGLER; BERNICE NOBLE; MURRAY W. STINSON

1999-01-01

326

Interleukin8 and Tumor Necrosis Factor Alpha Production in Human Epidermal Keratinocytes Induced by Trichophyton mentagrophytes  

Microsoft Academic Search

The keratinized tissues of skin and hair of humans and animals are commonly infected with dermatophytes. The phys- ical and chemical structure of the skin represents a form of defense barrier against fungal pathogens. A cutaneous immune system is probably responsible for initiating immune responses that work to prevent and to eliminate the infecting organisms (16). In addition, such responses

Yuka Nakamura; Rui Kano; Atsuhiko Hasegawa; Shinichi Watanabe

2002-01-01

327

Robust, inducible cardiac preferred expression system for transgenesis  

US Patent & Trademark Office Database

The methods and compositions of the present invention find use in altering cardiac-preferred expression in transgenic animals. The compositions of the invention include isolated nucleic acid molecules, expression cassettes, animal cells, transgenic animals, and transgenic mice. The transgenic animals of the invention exhibit inducible cardiac preferred expression of a nucleotide sequence of interest. The methods allow generation of transgenic animals with altered cardiac preferred expression of the nucleotide sequence of interest. In particular, the invention provides a method for altering the susceptibility of a transgenic animal to cardiopathy. A transgenic animal of the invention finds use in identifying anti-cardiopathic compounds.

2006-07-18

328

The effect of the pro-inflammatory cytokine tumor necrosis factor-alpha on human joint capsule myofibroblasts  

PubMed Central

Introduction Previous studies have shown that the number of myoblastically differentiated fibroblasts known as myofibroblasts (MFs) is significantly increased in stiff joint capsules, indicating their crucial role in the pathogenesis of post-traumatic joint stiffness. Although the mode of MFs' function has been well defined for different diseases associated with tissue fibrosis, the underlying mechanisms of their regulation in the pathogenesis of post-traumatic joint capsule contracture are largely unknown. Methods In this study, we examined the impact of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-?) on cellular functions of human joint capsule MFs. MFs were challenged with different concentrations of TNF-? with or without both its specifically inactivating antibody infliximab (IFX) and cyclooxygenase-2 (COX2) inhibitor diclofenac. Cell proliferation, gene expression of both alpha-smooth muscle actin (?-SMA) and collagen type I, the synthesis of prostaglandin derivates E2, F1A, and F2A, as well as the ability to contract the extracellular matrix were assayed in monolayers and in a three-dimensional collagen gel contraction model. The ?-SMA and COX2 protein expressions were evaluated by immunofluorescence staining and Western blot analysis. Results The results indicate that TNF-? promotes cell viability and proliferation of MFs, but significantly inhibits the contraction of the extracellular matrix in a dose-dependent manner. This effect was associated with downregulation of ?-SMA and collagen type I by TNF-? application. Furthermore, we found a significant time-dependent upregulation of prostaglandin E2 synthesis upon TNF-? treatment. The effect of TNF-? on COX2-positive MFs could be specifically prevented by IFX and partially reduced by the COX2 inhibitor diclofenac. Conclusions Our results provide evidence that TNF-? specifically modulates the function of MFs through regulation of prostaglandin E2 synthesis and therefore may play a crucial role in the pathogenesis of joint capsule contractures.

2010-01-01

329

Idiopathic recurrent pericarditis treated successfully with tumour necrosis factor alpha blocking agents (anti-TNF-?).  

PubMed

Idiopathic recurrent pericarditis (IRP) is defined by 2 or more episodes of acute pericarditis of unknown etiology. Either auto-immune or auto-inflammatory diseases are suspected. Usually, non-steroidal anti-inflammatory drugs, colchicine or low dose steroid treatments are effective, however, side effects and/or non-response patients are frequent. We report on three paedriatic patients with IRP from our paediatric rheumatology unit. The patients were non-responders to standard therapy and were treated with tumour necrosis factor alpha blocking agents (anti-TNF-?) and showed significant improvement. In two patients, the treatment was tapered and then stopped following several years of therapy. Symptoms flared in the last patient when therapy was tapered more quickly. We conclude that anti-TNF-? can be useful in selected cases of IRP. PMID:23711245

Nieto González, Juan Carlos; Monteagudo Saez, Indalecio; López-Longo, Francisco Javier; Serrano, Belén; Mata Martínez, Carmen; Carreño Pérez, Luis

2013-05-27

330

Immunoelectron microscopic localisation of transforming growth factor alpha in rat colon.  

PubMed Central

Transforming growth factor alpha (TGF alpha) is a polypeptide, which binds to the epidermal growth factor receptor to carry out its function related to cell proliferation and differentiation. The ultrastructural localisation of TGF alpha was studied in both the proximal and the distal colon. The columnar cells, lining the surface epithelium of the proximal colon, showed a strong immunoreactivity in the polyribosomes and in the interdigitations of the lateral membrane. The columnar cells of the crypts and the goblet cells in both the proximal and the distal colon showed the immunostaining in the cis and trans cisternae of the Golgi apparatus. TGF alpha seems to be processed differently in the surface columnar cells and in the crypt columnar cells and goblet cells. Moreover, it probably has different roles in proliferation and differentiation. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7

Perez-Tomas, R; Cullere, X; Asbert, M; Diaz-Ruiz, C

1994-01-01

331

Effect of transforming growth factor-alpha on inositol phospholipid metabolism in human epidermoid carcinoma cells  

SciTech Connect

Transforming growth factor-alpha (TGF-alpha) stimulates (in a dose-dependent manner) the incorporation of (/sup 32/P)Pi into phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bisphosphate (PIP2), and phosphatidic acid (PA) in the human epidermoid carcinoma cell line (A431). The effect of TGF-alpha on the incorporation was found to be similar to that of EGF. On the other hand, a striking difference in the activation of diacylglycerol (DG) kinase activity was seen between TGF-alpha and EGF. At least 100 times more TGF-alpha was required to achieve maximal stimulation of DG kinase activity relative to EGF. These results suggest that the activation of DG kinase by TGF-alpha may involve a mechanism independent from or subsequent to activation of the EGF receptor.

Kato, M.; Takenawa, T.; Twardzik, D.R.

1988-08-01

332

Polymorphisms in tumour necrosis factor alpha (TNFalpha) gene in patients with acute pancreatitis.  

PubMed

Proinflammatory cytokines, such as tumour necrosis factor alpha (TNFalpha), play fundamental roles in the pathogenesis of acute pancreatitis (AP). The aim of this study was to determine if polymorphisms in the TNFalpha gene are associated with AP. Two polymorphisms located in the promoter region (positions -308 and -238) in TNFalpha gene were determined using polymerase chain reaction- (PCR-) restriction fragment length polymorphism (RFLP) methods in 103 patients with AP and 92 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression analysis adjusted for age, sex, BMI and smoking. The frequencies of TNFalpha polymorphisms were both similar in patients with mild or severe pancreatitis, so were in pancreatitis patients and in controls. We suggest that both SNPs of TNFalpha are not genetic risk factor for AP susceptibility (OR = 1.63; 95% CI: 1.13-4.01 for TNFalpha(-308) and OR = 0.86; 95% CI: 0.75-1.77 for TNFalpha(-238)). PMID:20396411

Ozhan, Gül; Yanar, Hakan T; Ertekin, Cemalettin; Alpertunga, Buket

2010-04-14

333

Use of anti tumor necrosis factor-alpha monoclonal antibody for ulcerative jejunoileitis  

PubMed Central

Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain, weight loss associated with diarrhea, and multiple inflammatory ulcerations and strictures of the small bowel. Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo. Increased levels of tumor necrosis factor-alpha (TNF-?) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder. No specific therapy has been shown to change the course of ulcerative jejunoileitis. We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies, including high dose corticosteroids and cyclosporine. The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-? monoclonal antibody, infliximab (Remicade®).

Seven, Gulseren; Assaad, Adel; Biehl, Thomas; Kozarek, Richard A

2012-01-01

334

Use of anti tumor necrosis factor-alpha monoclonal antibody for ulcerative jejunoileitis.  

PubMed

Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain, weight loss associated with diarrhea, and multiple inflammatory ulcerations and strictures of the small bowel. Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo. Increased levels of tumor necrosis factor-alpha (TNF-?) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder. No specific therapy has been shown to change the course of ulcerative jejunoileitis. We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies, including high dose corticosteroids and cyclosporine. The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-? monoclonal antibody, infliximab (Remicade(®)). PMID:23049226

Seven, Gulseren; Assaad, Adel; Biehl, Thomas; Kozarek, Richard A

2012-09-28

335

Novel pathways that regulate tumor necrosis factor-alpha production in rheumatoid arthritis.  

PubMed

Clinical intervention studies have clearly shown the benefit in suppressing tumor necrosis factor-alpha (TNF-alpha) rheumatoid arthritis (RA). In consequence, considerable interest has arisen in those pathways that in turn regulate TNF-alpha production, because they may offer further possible therapeutic targets. Several candidate pathways are currently being investigated. They include T cell/macrophage interactions mediated primarily through cell-cell membrane contact; novel cytokine activities; microbial-derived products, in particular bacterial deoxyribonucleic acid sequences; autoreactive T cells, and immunoglobulins. At the subcellular level, there is further interest in targeting signaling and mRNA processing and cytokine cleavage pathways required for optimal TNF-alpha production. The key recent observations in these areas, particularly in the extracellular compartment, are reviewed. PMID:11981325

Gracie, J Alastair; Leung, Bernard P; McInnes, Iain B

2002-05-01

336

A riboswitch-based inducible gene expression system for mycobacteria.  

PubMed

Research on the human pathogen Mycobacterium tuberculosis (Mtb) would benefit from novel tools for regulated gene expression. Here we describe the characterization and application of a synthetic riboswitch-based system, which comprises a mycobacterial promoter for transcriptional control and a riboswitch for translational control. The system was used to induce and repress heterologous protein overexpression reversibly, to create a conditional gene knockdown, and to control gene expression in a macrophage infection model. Unlike existing systems for controlling gene expression in Mtb, the riboswitch does not require the co-expression of any accessory proteins: all of the regulatory machinery is encoded by a short DNA segment directly upstream of the target gene. The inducible riboswitch platform has the potential to be a powerful general strategy for creating customized gene regulation systems in Mtb. PMID:22279533

Seeliger, Jessica C; Topp, Shana; Sogi, Kimberly M; Previti, Mary L; Gallivan, Justin P; Bertozzi, Carolyn R

2012-01-18

337

Influenza virus infection induces cellular Ebp1 gene expression.  

PubMed

Influenza virus RNA-dependent RNA polymerase is composed of three viral proteins, PB1, PB2, and PA. The host protein Ebp1 (ErbB3-binding protein1) interacts with PB1, and inhibits both in vitro RNA synthesis and virus replication. On Western blotting, the induction of Ebp1 was observed after influenza virus infection. To understand the induction of Ebp1 by influenza virus infection, we introduced a series of deletions within the 981-nucleotide long sequence located upstream of the Ebp1 gene (-664 to +317 nt from the transcription initiation site) and ligated them to the GFP gene. GFP expression assays indicated that the 981-nt upstream region was required for expression of GFP in not all cells but some cells. Microscopic analysis of the transformants showed that GFP expression was up-regulated by the influenza virus infection. Furthermore, quantitative real-time PCR indicated that influenza virus infection induced Ebp1 mRNA expression. Our data showed that (i) the newly synthesized vRNP of influenza virus induces Ebp1 expression; (ii) the Ebp1 promoter localizes between -664 nt and the initiation site of the Ebp1 gene, +317-nt long sequence in the noncoding region is required for regulation of Ebp1 gene expression; and (iii) Ebp1 expression level is correlated with virus protein expression level. PMID:21794029

Ejima, Miho; Kadoi, Koji; Honda, Ayae

2011-07-28

338

Sulphate can induce differential expression of thioglucoside glucohydrolases (myrosinases)  

Microsoft Academic Search

Thioglucoside glucohydrolase (EC 3.2.3.1; myrosinase) hydrolyses glucosinolates and thereby liberates glucose and sulphur\\u000a and nitrogen compounds. To examine the hypothesis that the myrosinase-glucosinolate system is influenced by environmental\\u000a factors, the effect of sulphate on the expression of myrosinases was examined. On examining different plant organs at various\\u000a stages, it was observed that sulphate induces a differential expression of myrosinase polypeptides

A. M. Bones; S. Visvalingam; O. P. Thangstad

1994-01-01

339

Expression of amelin and trauma-induced dentin formation  

Microsoft Academic Search

According to recent studies, amelin (ameloblastin, sheathlin) is expressed in young odontoblasts at the initiation of dentin formation during odontogenesis. The purpose of the present investigation was to study whether amelin is also expressed at the onset of trauma-induced reparative dentin formation. The mandibular developing first molars of 5-day-old rats were surgically taken out, and their pulp tissue briefly separated

A. Spahr; S. P. Lyngstadaas; I. Slaby; B. Haller; C. Boeckh; F. Tsoulfidou; L. Hammarström

2002-01-01

340

Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis  

Microsoft Academic Search

Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. Osteopontin is an arginine-glycine-aspartate (RGD) containing secreted phosphoprotein recently shown to stimulate a local macrophage influx when injected subcutaneously in mice. We examined the effect of angiotensin II infusion on renal injury and osteopontin expression in the rat kidney by in situ hybridization and immunohistochemistry. Preceding pathologic changes in tubular and interstitial cells,

Cecilia M Giachelli; Raimund Pichler; Donna Lombardi; David T Denhardt; Charles E Alpers; Stephen M Schwartz; Richard J Johnson

1994-01-01

341

Mapping vocal communication pathways in birds with inducible gene expression  

Microsoft Academic Search

Expression mapping of activity-dependent genes has been very useful to reveal brain activation patterns associated with specific stimuli or behavioral contexts. In addition, activity-induced neuronal gene expression is likely associated with neuronal plasticity and may be part of the mechanism(s) involved in long-term memory formation. Analysis of the immediate-early gene zenk has been used to generate high-resolution maps of brain

C. V. Mello

2002-01-01

342

Ganoderma lucidum inhibits inducible nitric oxide synthase expression in macrophages  

Microsoft Academic Search

Nitric oxide (NO) is a principal mediator in many physiological and pathological processes. Overproduction of NO via the inducible nitric oxide synthase (iNOS) has cytotoxic effect through the formation of peroxynitrite with superoxide anion. The iNOS is mainly expressed in macrophages and is able to produce large amount of NO. The expression of iNOS is mainly regulated at the transcriptional

Connie W. H. Woo; Ricky Y. K. Man; Yaw L. Siow; Patrick C. Choy; Eric W. Y. Wan; Chak S. Lau; Karmin O

2005-01-01

343

Inducible nitric oxide synthase expression in human cerebral infarcts  

Microsoft Academic Search

The inducible or “immunological” isoform of nitric oxide synthase (iNOS) is induced in many cell types by inflammatory stimuli\\u000a and synthesizes toxic amounts of NO. In rodent models of focal cerebral ischemia, iNOS is expressed in neutrophils invading\\u000a the injured brain and in local blood vessels. Studies with iNOS inhibitors and iNOS null mice indicate that NO produced by\\u000a iNOS

Colleen Forster; H. Brent Clark; M. Elizabeth Ross; Constantino Iadecola

1999-01-01

344

A steroid-inducible gene expression system for plant cells.  

PubMed Central

Promoters that allow the selective induction of gene expression in vivo constitute an important methodology in eukaryotic organisms such as yeast and the fruit fly, but to date no such system has been described for higher plants. Given the fact that mammalian steroid receptors can function as hormone-dependent inducers of gene expression in heterologous systems, the feasibility of using mammalian steroid hormones as selective inducers of plant gene expression was investigated. Here it is shown that the glucocorticoid receptor expressed in plant cells is capable of activating a test gene linked to glucocorticoid response elements, providing the transfected plant cells are treated with glucocorticoid hormone. Nanomolar concentrations of glucocorticoids are sufficient to induce gene expression more than 150-fold, without causing detectable alterations in the physiology of the cultured plant cells. These findings indicate that glucocorticoid induction of steroid-responsive promoters should provide a general method for regulating gene expression in plant cells and imply that such a system might ultimately function in whole plants such as Arabidopsis thaliana. Images

Schena, M; Lloyd, A M; Davis, R W

1991-01-01

345

Short-Lived Effector CD8 T Cells Induced by Genetically Attenuated Malaria Parasite Vaccination Express CD11c.  

PubMed

Vaccination with a single dose of genetically attenuated malaria parasites can induce sterile protection against sporozoite challenge in the rodent Plasmodium yoelii model. Protection is dependent on CD8(+) T cells, involves perforin and gamma interferon (IFN-?), and is correlated with the expansion of effector memory CD8(+) T cells in the liver. Here, we have further characterized vaccine-induced changes in the CD8(+) T cell phenotype and demonstrated significant upregulation of CD11c on CD3(+) CD8b(+) T cells in the liver, spleen, and peripheral blood. CD11c(+) CD8(+) T cells are predominantly CD11a(hi) CD44(hi) CD62L(-), indicative of antigen-experienced effector cells. Following in vitro restimulation with malaria-infected hepatocytes, CD11c(+) CD8(+) T cells expressed inflammatory cytokines and cytotoxicity markers, including IFN-?, tumor necrosis factor alpha (TNF-?), interleukin-2 (IL-2), perforin, and CD107a. CD11c(-) CD8(+) T cells, on the other hand, expressed negligible amounts of all inflammatory cytokines and cytotoxicity markers tested, indicating that CD11c marks multifunctional effector CD8(+) T cells. Coculture of CD11c(+), but not CD11c(-), CD8(+) T cells with sporozoite-infected primary hepatocytes significantly inhibited liver-stage parasite development. Tetramer staining for the immunodominant circumsporozoite protein (CSP)-specific CD8(+) T cell epitope demonstrated that approximately two-thirds of CSP-specific cells expressed CD11c at the peak of the CD11c(+) CD8(+) T cell response, but CD11c expression was lost as the CD8(+) T cells entered the memory phase. Further analyses showed that CD11c(+) CD8(+) T cells are primarily KLRG1(+) CD127(-) terminal effectors, whereas all KLRG1(-) CD127(+) memory precursor effector cells are CD11c(-) CD8(+) T cells. Together, these results suggest that CD11c marks a subset of highly inflammatory, short-lived, antigen-specific effector cells, which may play an important role in eliminating infected hepatocytes. PMID:23980113

Cooney, Laura A; Gupta, Megha; Thomas, Sunil; Mikolajczak, Sebastian; Choi, Kimberly Y; Gibson, Claire; Jang, Ihn K; Danziger, Sam; Aitchison, John; Gardner, Malcolm J; Kappe, Stefan H I; Wang, Ruobing

2013-08-26

346

Thiostrepton-induced gene expression in Streptomyces lividans.  

PubMed Central

Thiostrepton induced the expression of four proteins (17, 19, 30, and 56 kilodaltons) of unknown function in Streptomyces lividans. The chromosomal gene which encoded the 19-kilodalton protein (tipA) was cloned and sequenced. Transcription of the tipA promoter was induced at least 200-fold by thiostrepton. The tipA 200-fold by thiostrepton. The tipA transcriptional start site (located by S1 mapping and primer extension experiments) was preceded by a 45-base-pair imperfect inverted-repeat sequence which included the -10 and -35 regions of the promoter. Under noninducing conditions in vivo, this might form a cruciform structure which is not recognized by RNA polymerase. A 143-base-pair fragment including this region was cloned into a promoter probe vector, pIJ486. In this plasmid, pAK114, the thiostrepton-inducible tipA promoter controlled the expression of a kanamycin resistance gene encoding an aminoglycoside phosphotransferase. As little as 1 ng of thiostrepton spotted on a lawn of S. lividans(pAK114) induced kanamycin-resistant growth. Other thiostreptonlike antibiotics also induced tipA, but structurally unrelated antibiotics which inhibit translation had no effect. In S. lividans, the promoter could be induced by thiostrepton during either growth or stationary phase. The tipA promoter should be a valuable tool for expression studies in streptomycetes. Images

Murakami, T; Holt, T G; Thompson, C J

1989-01-01

347

Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice.  

PubMed Central

Tolerance to peripheral antigens is thought to result from the inability of parenchymal tissue to stimulate T cells--an inability that is believed to relate to the lack of expression of the costimulatory signal(s) required for T-cell activation. To test this model, we generated transgenic mice expressing costimulatory molecule B7-1 on the B cells of the pancreas. We find that islets from these transgenic mice are immunogenic for naive T cells in vitro and in vivo. Nonetheless, mice expressing the costimulator B7-1 specifically on beta cells do not develop diabetes, suggesting that expression of the B7-1 costimulator is not sufficient to abrogate the tolerance to peripheral antigens. We have reported that tumor necrosis factor alpha subunit (TNF-alpha) expressed by beta cells leads to a local inflammation but no islet destruction. Strikingly, however, the combination of a local inflammation due to the expression of the cytokine TNF-alpha and the expression of B7-1 results in tissue destruction and diabetes. Images

Guerder, S; Picarella, D E; Linsley, P S; Flavell, R A

1994-01-01

348

Analysis of p60 and p80 tumor necrosis factor-alpha receptor messenger RNA and protein in human placentas.  

PubMed Central

Tumor necrosis factor-alpha (TNF), a pleiotrophic, multifunctional polypeptide factor, has been reported in both normal and infected human placentas. To identify potential targets for this cytokine, the cells in early and late gestation placentas and extraplacental membranes that express the two TNF receptor (TNF-R) genes, p60 and p80, were identified by using in situ hybridization and immunocytochemistry. Gestation-related, cell lineage-specific differences in steady-state levels of p60 and p80 TNF-R messenger RNA were observed. p60 TNF-R messenger RNA predominated at both early and late stages of gestation, being high in both mesenchymal and trophoblastic cell lineages. By contrast, p80 TNF-R messenger RNA was abundant only in intermittent stretches of first trimester syncytiotrophoblast and term placental mesenchymal cells. Overall, intensities of the TNF-R hybridization signals were stronger in term than in first trimester tissues. Transcription of the two TNF-R genes was confirmed by Northern blot hybridization. Translation was verified in all samples by immunohistology using polyclonal antibodies specific for the receptor proteins. p60 and p80 TNF-R proteins were identified both intracellularly and in maternal and fetal blood. Because TNF-Rs exist in both membrane-bound and soluble forms, the results of this study are consistent with the postulate that placental TNF-R have two critical functions: 1) modulation of TNF utilization by specific placental cell lineages during the course of pregnancy; and 2) protection against excessive TNF produced during infections. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Yelavarthi, K. K.; Hunt, J. S.

1993-01-01

349

Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor alpha promoter in vivo.  

PubMed

Tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of both acute and chronic inflammatory diseases and has been a target for the development of new anti-inflammatory drugs. Shikonins, the naphthoquinone pigments present in the root tissues of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), have been reported to exert anti-inflammatory effects both in vitro and in vivo. In this study, we evaluated the effects of shikonin and its derivatives on the transcriptional activation of human TNF-alpha promoter in a gene gun-transfected mouse skin system by using a luciferase reporter gene assay. The crude plant extract of L. erythrorhizon as well as derived individual compounds shikonin, isobutyryl shikonin, acetyl shikonin, dimethylacryl shikonin and isovaleryl shikonin showed significant dose-dependent inhibition of TNF-alpha promoter activation. Among the tested compounds, shikonin and isobutyryl shikonin exhibited the highest inhibition of TNF-alpha promoter activation and also showed significant suppression of transgenic human TNF-alpha mRNA expression and protein production. We demonstrated that shikonin-inhibitory response was retained in the core TNF-alpha promoter region containing the TATA box and a 48-bp downstream sequence relative to the transcription start site. Further our results indicated that shikonin suppressed the basal transcription and activator-regulated transcription of TNF-alpha by inhibiting the binding of transcription factor IID protein complex (TATA box-binding protein) to TATA box. These in vivo results suggest that shikonins inhibit the transcriptional activation of the human TNF-alpha promoter through interference with the basal transcription machinery. Thus, shikonins may have clinical potential as anti-inflammatory therapeutics. PMID:14645256

Staniforth, Vanisree; Wang, Sheng-Yang; Shyur, Lie-Fen; Yang, Ning-Sun

2003-11-25

350

The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells.  

PubMed

Constitutive expression of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is characteristic of malignant ovarian surface epithelium. We investigated the hypothesis that this autocrine action of TNF-alpha generates and sustains a network of other mediators that promote peritoneal cancer growth and spread. When compared with two ovarian cancer cell lines that did not make TNF-alpha, constitutive production of TNF-alpha was associated with greater release of the chemokines CCL2 and CXCL12, the cytokines interleukin-6 (IL-6) and macrophage migration-inhibitory factor (MIF), and the angiogenic factor vascular endothelial growth factor (VEGF). TNF-alpha production was associated also with increased peritoneal dissemination when the ovarian cancer cells were xenografted. We next used RNA interference to generate stable knockdown of TNF-alpha in ovarian cancer cells. Production of CCL2, CXCL12, VEGF, IL-6, and MIF was decreased significantly in these cells compared with wild-type or mock-transfected cells, but in vitro growth rates were unaltered. Tumor growth and dissemination in vivo were significantly reduced when stable knockdown of TNF-alpha was achieved. Tumors derived from TNF-alpha knockdown cells were noninvasive and well circumscribed and showed high levels of apoptosis, even in the smallest deposits. This was reflected in reduced vascularization of TNF-alpha knockdown tumors. Furthermore, culture supernatants from such cells failed to stimulate endothelial cell growth in vitro. We conclude that autocrine production of TNF-alpha by ovarian cancer cells stimulates a constitutive network of other cytokines, angiogenic factors, and chemokines that may act in an autocrine/paracrine manner to promote colonization of the peritoneum and neovascularization of developing tumor deposits. PMID:17234767

Kulbe, Hagen; Thompson, Richard; Wilson, Julia L; Robinson, Stephen; Hagemann, Thorsten; Fatah, Rewas; Gould, David; Ayhan, Ayse; Balkwill, Frances

2007-01-15

351

The role of tumor necrosis factor-alpha in systemic lupus erythematosus  

PubMed Central

Murine models of systemic lupus erythematosus (SLE) have shown apparently contradictory evidence in that either (a) tumor necrosis factor (TNF) expression was low and TNF administration helpful or (b) TNF was high and TNF blockade of therapeutic benefit, depending on the mouse model investigated. In fact, TNF apparently has both effects, checking autoimmunity, at least to some degree, and fostering inflammation. TNF blockade regularly, but transiently, induces or increases autoantibodies to chromatin and to phospholipids. At the same time, open-label data suggest that TNF blockade suppresses inflammatory manifestations of SLE, and long-term benefit was seen in patients with lupus nephritis. A controlled clinical trial is under way.

Aringer, Martin; Smolen, Josef S

2008-01-01

352

Increased lung inflation induces gene expression after pneumonectomy.  

PubMed

Rapid hyperplastic growth of the remaining lung is initiated by partial pneumonectomy in many mammalian species. The response restores normal tissue structure and function. Although physiological control of compensatory lung growth is documented, little is known about the molecular mechanisms that underlie the process. The aim of this study was to investigate the role of mechanical signals in the induction of immediate-early gene (IEG) expression after pneumonectomy. Expression of c-fos and junB increased nine- and fourfold, respectively, in the right lung within 30 min after left pneumonectomy in rats. In contrast, changes in expression of c-jun and c-myc were not observed. When isolated lungs were subjected to elevated airway pressures in vitro, expression of c-fos and junB was induced in a time- and dose-dependent manner similar to that observed in vivo. Similarly, in vitro lung perfusion induced c-fos and junB expression in the absence of increasing lung inflation. These results support the premise that rapid changes in IEG expression after pneumonectomy are initiated by mechanical signaling in the remaining lung. Elevated IEG expression may contribute to initiation of compensatory lung growth. PMID:9688931

Gilbert, K A; Rannels, D E

1998-07-01

353

Granulocyte-Macrophage Colony-Stimulating Factor- and Tumor Necrosis Factor Alpha-Mediated Matrix Metalloproteinase Production by Human Osteoblasts and Monocytes after Infection with Brucella abortus ?  

PubMed Central

Osteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. Since matrix metalloproteinases (MMPs) are involved in joint and bone damage in inflammatory and infectious diseases, we investigated the production of MMPs by human osteoblasts and monocytes, either upon Brucella abortus infection or upon reciprocal stimulation with factors produced by each infected cell type. B. abortus infection of the normal human osteoblastic cell line hFOB 1.19 triggered a significant release of MMP-2, which was mediated in part by granulocyte-macrophage colony-stimulating factor (GM-CSF) acting on these same cells. Supernatants from infected osteoblasts exhibited increased levels of monocyte chemoattractant protein 1 and induced the migration of human monocytes (THP-1 cell line). Infection with B. abortus induced a high MMP-9 secretion in monocytes, which was also induced by heat-killed B. abortus and by the Omp19 lipoprotein from B. abortus. These effects were mediated by Toll-like receptor 2 and by the action of tumor necrosis factor alpha (TNF-?) produced by these same cells. Supernatants from B. abortus-infected monocytes induced MMP-2 secretion in uninfected osteoblasts, and this effect was mediated by TNF-?. Similarly, supernatants from infected osteoblasts induced MMP-9 secretion in uninfected monocytes. This effect was mediated by GM-CSF, which induced TNF-? production by monocytes, which in turn induced MMP-9 in these cells. These results suggest that MMPs could be potentially involved in the tissue damage observed in osteoarticular brucellosis.

Scian, Romina; Barrionuevo, Paula; Giambartolomei, Guillermo H.; Fossati, Carlos A.; Baldi, Pablo C.; Delpino, M. Victoria

2011-01-01

354

Inorganic Polyphosphate Suppresses Lipopolysaccharide-Induced Inducible Nitric Oxide Synthase (iNOS) Expression in Macrophages  

PubMed Central

In response to infection, macrophages produce a series of inflammatory mediators, including nitric oxide (NO), to eliminate pathogens. The production of these molecules is tightly regulated via various mechanisms, as excessive responses are often detrimental to host tissues. Here, we report that inorganic polyphosphate [poly(P)], a linear polymer of orthophosphate ubiquitously found in mammalian cells, suppresses inducible nitric oxide synthase (iNOS) expression induced by lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, in mouse peritoneal macrophages. Poly(P) with longer chains is more potent than those with shorter chains in suppressing LPS-induced iNOS expression. In addition, poly(P) decreased LPS-induced NO release. Moreover, poly(P) suppressed iNOS mRNA expression induced by LPS stimulation, thereby indicating that poly(P) reduces LPS-induced iNOS expression by down-regulation at the mRNA level. In contrast, poly(P) did not affect the LPS-induced release of TNF, another inflammatory mediator. Poly(P) may serve as a regulatory factor of innate immunity by modulating iNOS expression in macrophages.

Harada, Kana; Shiba, Toshikazu; Doi, Kazuya; Morita, Koji; Kubo, Takayasu; Makihara, Yusuke; Piattelli, Adriano; Akagawa, Yasumasa

2013-01-01

355

Gene expression profiling of murine hepatic steatosis induced by tamoxifen  

Microsoft Academic Search

Tamoxifen is an antiestrogenic agent used widely in the treatment of estrogen receptor-positive breast cancer. However, hepatic steatosis has been reported during clinical trials of tamoxifen. To explore the mechanism responsible for this tamoxifen-induced hepatic steatosis, we used microarray analysis to profile the gene expression pattern of mouse liver after tamoxifen treatment. Tamoxifen was administered orally as a single dose

Min-Ho Lee; Ji-Won Kim; Ju-Han Kim; Kyung-Sun Kang; Gu Kong; Mi-Ock Lee

2010-01-01

356

Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants  

Microsoft Academic Search

Microarray technology continues to gain increased acceptance in the drug development process, particularly at the stage of toxicology and safety assessment. In the current study, microarrays were used to investigate gene expression changes associated with hepatotoxicity, the most commonly reported clinical liability with pharmaceutical agents. Acetaminophen, methotrexate, methapyrilene, furan and phenytoin were used as benchmark compounds capable of inducing specific

Qihong Huang; Xidong Jin; Elias T Gaillard; Brian L Knight; Franklin D Pack; James H Stoltz; Supriya Jayadev; Kerry T Blanchard

2004-01-01

357

Epidermal growth factor or transforming growth factor alpha is required for kidney tubulogenesis in matrigel cultures in serum-free medium.  

PubMed Central

The ability of matrigel, a reconstituted basement membrane gel, to induce the differentiation of baby mouse kidney cells has been examined in a hormonally defined serum-free medium. Primary cultures of baby mouse kidney cells were observed to form tubules over a time interval of 1-2 weeks in matrigel. Electron microscopic studies showed that tubules with lumens were present, and the tubule morphology was similar to that of the collecting duct. When using matrigel from which the growth factors had been removed, tubule formation no longer occurred, unless the medium was further supplemented with epidermal growth factor (10 ng/ml). Transforming growth factor alpha stimulated tubule formation as effectively as epidermal growth factor, whereas transforming growth factor beta had an inhibitory effect on tubule formation. These data suggest that both an extracellular matrix and specific growth factors may regulate kidney differentiation during development. Images

Taub, M; Wang, Y; Szczesny, T M; Kleinman, H K

1990-01-01

358

Mercury induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase.  

PubMed

Nuclear factor-?B (NF-?B) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. NF-?B activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The divalent heavy metal mercury has been used for thousands of years. Although mercury is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that mercury alone induces NF-?B activation, resulting in the induced expression of COX-2 and iNOS. The results suggest that mercury can induce inflammatory diseases by lowering host defense. PMID:22080037

Park, Hye-Jeong; Youn, Hyung-Sun

2011-11-11

359

Thyrotropin modifies activation of nuclear factor kappaB by tumour necrosis factor alpha in rat thyroid cell line.  

PubMed Central

We have recently demonstrated that nuclear factor kappaB (NF-kappaB) mediates the tumour necrosis factor alpha (TNF-alpha)-dependent expression of the gene encoding interleukin 6 (IL-6) in rat thyroid FRTL-5 cells cultured in the presence of thyrotropin (TSH). In the present study we investigated how TSH is involved in the activation of NF-kappaB by TNF-alpha in the cells. Electrophoretic mobility-shift assay revealed that, in the absence of TSH, TNF-alpha activated a single protein-DNA complex containing the p50 subunit but not other NF-kappaB subunits such as p65. In contrast, two distinct protein-DNA complexes were activated in the presence of TSH: the faster-migrating complex contained only p50 subunit; the slower-migrating complex consisted of p65-p50 heterodimer. This TSH effect was mimicked by forskolin and thyroid-stimulating antibodies obtained from patients with Graves's disease, suggesting that an increase in intracellular cAMP is responsible for the induction of different NF-kappaBs by TNF-alpha. A transient transfection study with a luciferase reporter gene driven by multimerized NF-kappaB sites demonstrated that TNF-alpha increased the luciferase activities only in the presence of TSH, and that this increase was inhibited by the co-transfection of mutant p65, which prevented the function of wild-type p65 in a dominant-negative manner. Accordingly, TNF-alpha activated the expression of the IL-6 gene in the presence of TSH but not in its absence. Although the expression of the p105 gene, another known target for NF-kappaB, was increased by TNF-alpha in the absence of TSH, the presence of TSH further increased the mRNA level. Taken together, these observations indicate that the presence of TSH is crucial for the NF-kappaB-mediated actions of TNF-alpha on thyroid follicular cells.

Kikumori, T; Kambe, F; Nagaya, T; Funahashi, H; Seo, H

2001-01-01

360

An Essential Role for NF-kappaB in Preventing TNF-alpha-Induced Cell Death  

Microsoft Academic Search

Studies on mice deficient in nuclear factor kappa B (NF-kappaB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-alpha (TNF-alpha)-dependent genes. Treatment of RelA-deficient (RelA-\\/-) mouse fibroblasts and macrophages with TNF-alpha resulted in a significant reduction in

Amer A. Beg; David Baltimore

1996-01-01

361

Aldose reductase regulates TNF-?-induced inducible nitric oxide synthase expression in human mesangial cells  

Microsoft Academic Search

Glomerulonephritis is one of the most important causes of renal failure, which is accompanied with production of Nitric Oxide\\u000a (NO) synthesized by inducible nitric oxide synthase (iNOS). Aldose reductase (AR) is the key enzyme in polyol pathway and\\u000a plays an important role in glucose metabolism. Here, we report our finding that AR regulates tumor-necrosis-factor-?-induced\\u000a (TNF-?-induced) iNOS expression in human mesangial

Jingjing ZhaoTao; Tao Jiang; Hui Li; Yuejuan Zhang; Nong Zhang

362

Cellular and molecular evidence for a role of tumor necrosis factor alpha in the ovulatory mechanism of trout  

Microsoft Academic Search

BACKGROUND: The relevance of immune-endocrine interactions to the regulation of ovarian function in teleosts is virtually unexplored. As part of the innate immune response during infection, a number of cytokines such as tumor necrosis factor alpha (TNF alpha) and other immune factors, are produced and act on the reproductive system. However, TNF alpha is also an important physiological player in

Diego Crespo; Emilie Bonnet; Nerea Roher; Simon A MacKenzie; Aleksei Krasnov; Frederick W Goetz; Julien Bobe; Josep V Planas

2010-01-01

363

Human Cytomegalovirus Attenuates Interleukin1  and Tumor Necrosis Factor Alpha Proinflammatory Signaling by Inhibition of NF B Activation  

Microsoft Academic Search

Viral infection is associated with a vigorous inflammatory response characterized by cellular infiltration and release of the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-). In the present study, we identified a novel function of human cytomegalovirus (HCMV) that results in inhibition of IL-1 and TNF- signaling pathways. The effect on these pathways was limited to cells infected

Michael A. Jarvis; Jamie A. Borton; Amy M. Keech; John Wong; William J. Britt; Bruce E. Magun; Jay A. Nelson

2006-01-01

364

The Treponema denticola Surface Protease Dentilisin Degrades Interleukin1  (IL1 ), IL6, and Tumor Necrosis Factor Alpha  

Microsoft Academic Search

Dentilisin is a major surface protease and virulence factor of the bacterium Treponema denticola. In this study, we found that T. denticola reduced inflammatory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha, in peripheral blood mononuclear cells through degradation by dentilisin.

Meguru Miyamoto; Kazuyuki Ishihara; Katsuji Okuda

2006-01-01

365

Human immunodeficiency virus vectors for inducible expression of foreign genes.  

PubMed Central

Tat-dependent expression of an endogenous lethal or deleterious foreign gene might be useful for abrogating the production of human immunodeficiency virus (HIV) from cells. This type of HIV-induced cellular killing, as well as other approaches to gene therapy for HIV infection, would be facilitated by simple HIV vectors that express introduced genes in a Tat-inducible manner. As part of studies to examine the feasibility of this concept, we constructed HIV-1 vectors that express the hygromycin B phosphotransferase gene (Hygr) in a Tat-dependent manner. Comparison of the efficiency of propagation of each vector indicates that sequences extending into the gag open reading frame are necessary in cis for efficient vector propagation. Southern blot analysis of genomic DNA isolated from vector-infected cells demonstrated that the vectors were capable of being propagated as expected without gross rearrangements or deletions. A fragment of the influenza A virus hemagglutinin (H5 HA) gene, capable of eliciting antibody and cytotoxic T-cell responses, was used as a marker for further characterization of the vector system. A Tat-dependent vector conferring the H5 HA+ phenotype was assayed by indirect immunofluorescence, and cells which contained but did not express the H5 HA gene were isolated. The activation of H5 HA expression following HIV infection of Tat- cells that stably contained but did not express the H5 HA construct was determined to be an efficient process. Images

Buchschacher, G L; Panganiban, A T

1992-01-01

366

Inducible Expression of Cre Recombinase in the Retinal Pigmented Epithelium  

PubMed Central

PURPOSE The retinal pigmented epithelium (RPE) expresses many genes that play important roles in the support and maintenance of photoreceptors. The present study was conducted to develop a system amenable to the dissection of the temporal function of these genes, specifically within RPE cells. Transgenic mice were generated and characterized in which the expression of Cre recombinase could be specifically induced within the RPE. METHODS Transgenic mice carrying the human vitelliform macular dystrophy-2 (VMD2) promoter (PVMD2)–directed reverse tetracycline-dependent transactivator (rtTA) and the tetracycline-responsive element (TRE)–directed cre were generated. Inducible Cre expression was achieved by feeding doxycycline to these mice and was characterized by using a Cre-activatable lacZ reporter mouse strain (R26R). RESULTS A ?-galactosidase assay of rtTA/Cre-R26R mice demonstrated that the basal level of Cre expression without doxycycline induction was negligible. Addition of doxycycline led to induction of RPE-specific Cre expression/function at least from embryonic day 9 to postnatal day 60. The highest induction occurred at approximately postnatal day 4. As measured by ERG and histology, retinal function and morphology were normal in 10-month-old rtTA/Cre mice that were treated with doxycycline at weaning age. CONCLUSIONS Transgenic mice were generated that express Cre recombinase in the RPE in an inducible fashion. These mice will be useful for studies of the RPE-specific role of genes that are expressed in the RPE as well as other cells, particularly for avoiding embryonic lethality and dissecting the function of genes that play dual roles in development and adulthood.

Le, Yun-Zheng; Zheng, Wei; Rao, Peng-Cheng; Zheng, Lixing; Anderson, Robert E.; Esumi, Noriko; Zack, Donald J.; Zhu, Meili

2009-01-01

367

Phagocytosis of co-developing neutrophil progenitors by dendritic cells in a culture of human CD34(+) cells with granulocyte colony-stimulating factor and tumor necrosis factor-alpha.  

PubMed

Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce the differentiation of CD34(+) cells toward dendritic cells (DCs). We have previously shown that DCs are co-generated from human CD34(+) cells during erythroid or megakaryocytic differentiation in the presence of TNF-alpha, and those DCs are able to stimulate autologous T cell proliferation. The aim of this study was to learn whether the co-stimulation of granulocyte colony-stimulating factor (G-CSF) and TNF-alpha would generate neutrophil progenitors and DCs together from human CD34(+) cells, and if this was the case, to clarify the phenotypic and functional characteristics of these DCs. When highly purified human CD34(+) cells were cultured for 7 days with G-CSF alone, the generated cells predominantly expressed a granulocyte marker, CD15, and then differentiated into neutrophils after 14 days of culture. The addition of TNF-alpha with G-CSF markedly decreased the number of CD15(+) cells without affecting the total number of cells during 7 days of culture. Almost one third of the generated cells were positive for CD11c and CD123. Furthermore, CD11c(+) cells were found to phagocytose CD15(+) cells and were able to induce allogeneic, but not autologous, T cell proliferation in the mixed l