Metallothionein modulates lipopolysaccharide-stimulated tumour necrosis factor expression in mouse peritoneal macrophages

2002 ◽  
Vol 361 (2) ◽  
pp. 363-369 ◽  
Author(s):  
Masako KANEKIYO ◽  
Norio ITOH ◽  
Atsuko KAWASAKI ◽  
Akiko MATSUYAMA ◽  
Kimihiro MATSUDA ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Tumour Necrosis Factor ◽  
Inflammatory Cytokines ◽  
Metal Binding ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Peritoneal Macrophages ◽  
Tnf Α ◽  
Necrosis Factor

Metallothionein (MT) is a low-molecular-mass, cysteine-rich metal binding protein thought to be involved in the detoxification of heavy metals and scavenging of free radicals. MT is directly induced not only by heavy metals, but also by hormones and cytokines. The present study, which uses mice with genetic deletions of the MT proteins (MT−/- mice), was designed to evaluate the effects of MT on the expression of pro-inflammatory cytokines in macrophages. We found that the production of tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS) in peritoneal macrophages is up-regulated by MT via the modulation of nuclear factor κB (NF-κB) activity. This conclusion is supported by the following observations: (1) LPS stimulated the secretion of less TNF activity from MT−/- peritoneal exudate macrophages (PEMs) than from wild-type controls (MT+/+ mice) without a difference in the pattern of kinetics; (2) LPS-stimulated expression of TNF-α mRNA was decreased in MT−/- PEMs; (3) LPS-stimulated activation of NF-κB was decreased in MT−/- PEMs; and (4) production of TNF in PEMs of MT−/- mice after LPS treatment in vivo was decreased (compared with MT+/+ PEMs). Expression of other inflammatory cytokines, interleukin (IL)-1α and IL-6 mRNA, which were modulated by NF-κB, were also down-regulated in MT−/- PEMs. Thus MT plays a key role in the LPS-induced activation of PEMs via the modulation of NF-κB activity.

Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells

2014 ◽  
Vol 112 (09) ◽  
pp. 580-588 ◽  
Author(s):  
Sung Kyul Lee ◽  
Seung-Hee Yang ◽  
Il Kwon ◽  
Ok-Hee Lee ◽  
Ji Hoe Heo
Keyword(s):  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Necrosis Factor

SummaryTumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Thyrotropin modifies activation of nuclear factor κB by tumour necrosis factor α in rat thyroid cell line

2001 ◽  
Vol 354 (3) ◽  
pp. 573-579 ◽  
Author(s):  
Toyone KIKUMORI ◽  
Fukushi KAMBE ◽  
Takashi NAGAYA ◽  
Hiroomi FUNAHASHI ◽  
Hisao SEO
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Rat Thyroid ◽  
Factor Α ◽  
Necrosis Factor

We have recently demonstrated that nuclear factor κB (NF-κB) mediates the tumour necrosis factor α (TNF-α)-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-κB by TNF-α in the cells. Electrophoretic mobility-shift assay revealed that, in the absence of TSH, TNF-α activated a single protein–DNA complex containing the p50 subunit but not other NF-κB 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–p50heterodimer. 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-κBs by TNF-α. A transient transfection study with a luciferase reporter gene driven by multimerized NF-κB sites demonstrated that TNF-α 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-α 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-κB, was increased by TNF-α 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-κB-mediated actions of TNF-α on thyroid follicular cells.

scholarly journals Calcium-dependent regulation of tumour necrosis factor-alpha receptor signalling by copine

2004 ◽  
Vol 378 (3) ◽  
pp. 1089-1094 ◽  
Author(s):  
Jose Luis TOMSIG ◽  
Hitoshi SOHMA ◽  
Carl E. CREUTZ
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Competitive Inhibition ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Hek293 Cells ◽  
Ionophore A23187 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Necrosis Factor

The role of copines in regulating signalling from the TNF-α (tumour necrosis factor-α) receptor was probed by the expression of a copine dominant-negative construct in HEK293 (human embryonic kidney 293) cells. The construct was found to reduce activation of the transcription factor NF-κB (nuclear factor-κB) by TNF-α. The introduction of calcium into HEK293 cells either through the activation of muscarinic cholinergic receptors or through the application of the ionophore A23187 was found to enhance TNF-α-dependent activation of NF-κB. This effect of calcium was completely blocked by the copine dominant-negative construct. TNF-α was found to greatly enhance the expression of endogenous copine I, and the responsiveness of the TNF-α signalling pathway to muscarinic stimulation increased in parallel with the increased copine I expression. The copine dominant-negative construct also inhibited the TNF-α-dependent degradation of IκB, a regulator of NF-κB. All of the effects of the dominant-negative construct could be reversed by overexpression of full-length copine I, suggesting that the construct acts specifically through competitive inhibition of copine. One of the identified targets of copine I is the NEDD8-conjugating enzyme UBC12 (ubiquitin C12), that promotes the degradation of IκB through the ubiquitin ligase enzyme complex SCFβTrCP. Therefore the copine dominant-negative construct might inhibit TNF-α signalling by dysregulation or mislocalization of UBC12. Based on these results, a hypothesis is presented for possible roles of copines in regulating other signalling pathways in animals, plants and protozoa.

scholarly journals Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappaB activation

2003 ◽  
Vol 370 (3) ◽  
pp. 1011-1017 ◽  
Author(s):  
YunJin JUNG ◽  
Jennifer S. ISAACS ◽  
Sunmin LEE ◽  
Jane TREPEL ◽  
Zheng-gang LIU ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Protein Stabilization ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Interacting Protein ◽  
Tnf Α ◽  
Necrosis Factor

Tumour necrosis factor α (TNF-α) binds to its receptor (TNFR1) and activates both death- and inflammation/survival-related signalling pathways. The inflammation and survival-related signalling cascade results in the activation of the transcription factor, nuclear factor κB (NF-κB) and requires recruitment of receptor-interacting protein (RIP) to TNFR1. The indispensable role of RIP in TNF-induced NF-κB activation has been demonstrated in RIP-/- mice and in cell lines derived from such mice. In the present study, we show that the TNF-α-induced accumulation of hypoxia-inducible factor 1α (HIF-1α) protein in normoxic cells is RIP-dependent. Exposing fibroblasts derived from RIP-/- mice to either cobalt or PMA resulted in an equivalent HIF-1α induction to that seen in RIP+/+ fibroblasts. In contrast, RIP-/- cells were unable to induce HIF-1α in response to TNF-α. Further, transient transfection of NIH 3T3 cells with an NF-κB super-repressor plasmid (an inhibitor of NF-κB activation) also prevented HIF-1α induction by TNF-α. Surprisingly, although HIF-1α mRNA levels remained unchanged after induction by TNF, induction of HIF-1α protein by the cytokine was completely blocked by pretreatment with the transcription inhibitors actinomycin D and 5,6-dichlorobenzimidazole riboside. Finally, TNF failed to induce both HIF-1α, made resistant to von Hippel—Lindau (VHL), and wild-type HIF-1α transfected into VHL-/- cells. These results indicate that HIF-1α induction by TNF-α in normoxic cells is mediated by protein stabilization but is nonetheless uniquely dependent on NF-κB-driven transcription. Thus the results describe a novel mechanism of HIF-1α up-regulation and they identify HIF-1α as a unique component of the NF-κB-mediated inflammatory/survival response.

The effects of tumour necrosis factor on host—parasite relations in murine Mesocestoides corti (Cestoda) infection

Parasitology ◽  
1992 ◽  
Vol 105 (3) ◽  
pp. 453-459 ◽  
Author(s):  
P. Jenkins ◽  
S. Spiers ◽  
J. B. Dixon ◽  
S. D. Carter ◽  
S. May
Keyword(s):  
Tumour Necrosis Factor ◽  
Post Infection ◽  
Tumour Necrosis ◽  
Fold Increase ◽  
Peritoneal Macrophages ◽  
Hepatic Necrosis ◽  
Peritoneal Cells ◽  
Necrosis Factor

SUMMARYThe regulatory role of tumour necrosis factor (TNF) was investigated in murine infection with tetrathyridia of Mesocestoides corti. Recombinant TNFα reduced macrophage larvicidal activity in vitro. M. corti primed mice for TNF release in response to bacterial lipopolysaccharide (LPS) in vivo. TNF activity was amplified 100-fold at 14 days post-infection (p.i.), with a further rise at day 28 p.i. Maximal inflammatory reaction was observed histologically in the liver at the height of TNF activity. Hepatic necrosis was located within inflammatory foci, but not within the vicinity of the parasite itself, suggesting that TNF may contribute to the pathogenesis of infection. Peritoneal cells from infected mice, when stimulated with tetrathyridia in vitro, showed a 4-fold increase in TNFα activity at day 14 p.i. However, when peritoneal cells were stimulated with LPS in vitro, a marked increase in TNFα secretion was observed at 2 months post-infection followed by a slow decline. It is suggested that impaired macrophage effector function, previously attributed to endogenous endotoxin, which gains access to peritoneal macrophages through an inability of the liver to detoxify endotoxin, may be mediated through TNFα.

scholarly journals In vivo isolated kidney perfusion with tumour necrosis factor α (TNF-α) in tumour-bearing rats

1999 ◽  
Vol 79 (3-4) ◽  
pp. 433-439 ◽  
Author(s):  
A H van der Veen ◽  
A L B Seynhaeve ◽  
J Breurs ◽  
P T G A Nooijen ◽  
RL Marquet ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Tumour Necrosis Factor Α ◽  
Isolated Kidney ◽  
Tumour Bearing ◽  
Tnf Α ◽  
Kidney Perfusion ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals A pre-formed Pyrogenic Factor Released by Lipopolysaccharide Stimulated Macrophages

1994 ◽  
Vol 3 (5) ◽  
pp. 365-373 ◽  
Author(s):  
A. R. Zampronio ◽  
M. C. C. Melo ◽  
C. A. A. Silva ◽  
I. R. Pelá ◽  
S. J. Hopkins ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Peritoneal Macrophages ◽  
Maximal Response ◽  
Metal Levels ◽  
Necrosis Factor ◽  
Cu And Zn ◽  
Pyrogenic Activity

The aim of this study was to investigate the pyrogenic activity of factor(s) released by rat peritoneal macrophages following a brief stimulation with LPS. The effect of this factor on the number of circulating leukocytes and serum Fe, Cu and Zn levels, was also evaluated. The possibility that the content of interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF) in the supernatant could explain the observations was investigated. Supernatant produced over a period of 1 h by peritoneal macrophages, following a 30 min incubation with LPS at 37°C, was ultrafiltered through a 10 000 MW cut-off Amicon membrane, sterilized, and concentrated 2.5, 5, 10 and 20 times. The intravenous (i.v.) injection of this supernatant induced a concentration-dependent fever in rats with a maximal response at 2 h. The pyrogenic activity was produced by macrophages elicited with thioglycollate and by resident cells. The supernatants also induced neutrophilia and reduction in Fe and Zn 6 h after the injection. Absence of activity in boiled supernatants, or supernatants from macrophages incubated at 4°C with LPS, indicates that LPS was not responsible for the activity.In vitrotreatment with indomethacin (Indo), dexamethasone (Dex), or cycloheximide (Chx) did not modify the release of pyrogenic activity into the supernatant or its effects on the reduction in serum metal levels. Although Chx abolished the production of mediator(s) inducing neutrophilia, and Dex reduced the induction of IL-1β, TNF and IL-6, injection of the highest concentration of these cytokines detected in the supernatants did not induce fever.In vivotreatment with Dex, but not Indo, abolished the fever induced by the supernatant. These results suggest that macrophages contain pre-formed pyrogenic mediator(s), not related to IL-1β, IL-6 or TNF, that acts indirectly and independently of prostaglandtn. It also seems likely that the pyrogenic activity is related to the factor responsible for the reduction of serum Fe and Zn levels, but not the neutrophilia.

scholarly journals The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha

2004 ◽  
Vol 380 (3) ◽  
pp. 651-659 ◽  
Author(s):  
Hua LING ◽  
Anneliese D. RECKLIES
Keyword(s):  
Protein Kinase ◽  
Tumour Necrosis Factor ◽  
Inflammatory Cytokines ◽  
Tumour Necrosis ◽  
Nuclear Translocation ◽  
Interleukin 1 ◽  
Matrix Metalloproteases ◽  
Human Cartilage ◽  
Tnf Α ◽  
Necrosis Factor

Expression of the chitinase 3-like protein HC-gp39 (human cartilage glycoprotein 39) is associated with conditions of increased matrix turnover and tissue remodelling. High levels of this protein have been found in sera and synovial fluids of patients with inflammatory and degenerative arthritis. In order to assess the role of HC-gp39 in matrix degradation induced by inflammatory cytokines, we have examined its effect on the responses of connective tissue cells to TNF-α (tumour necrosis factor-α) and IL-1 (interleukin-1) with respect to activation of signalling pathways and production of MMPs (matrix metalloproteases) and chemokines. Stimulation of human skin fibroblasts or articular chondrocytes with IL-1 or TNF-α in the presence of HC-gp39 resulted in a marked reduction of both p38 mitogen-activated protein kinase and stress-activated protein kinase/Jun N-terminal kinase phosphorylation, whereas nuclear translocation of nuclear factor κB proceeded unimpeded. HC-gp39 suppressed the cytokine-induced secretion of MMP1, MMP3 and MMP13, as well as secretion of the chemokine IL-8. The suppressive effects of HC-gp39 were dependent on phosphoinositide 3-kinase activity, and treatment of cells with HC-gp39 resulted in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating kinase 1. This process could therefore be responsible for the down-regulation of cytokine signalling by HC-gp39. These results suggest a physiological role for HC-gp39 in limiting the catabolic effects of inflammatory cytokines.

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