IL-6 enhances TNF-alpha- and IL-1-induced increase of Mn superoxide dismutase mRNA and O2 tolerance

1992 ◽  
Vol 263 (1) ◽  
pp. L22-L26 ◽  
Author(s):  
M. F. Tsan ◽  
J. E. White ◽  
P. J. Del Vecchio ◽  
J. B. Shaffer
Keyword(s):  
Superoxide Dismutase ◽  
Endothelial Cell ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Sod Activity ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Tracheal Insufflation

Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1), and interleukin-6 (IL-6) are multifunctional cytokines produced by a number of cells in response to endotoxin. We have previously demonstrated (M.-F. Tsan, J. E. White, T. A. Santana, and C. Y. Lee. J. Appl. Physiol. 68: 1211–1219, 1990, and M.-F. Tsan, C. Y. Lee, and J. E. White. J. Appl. Physiol. 71: 688–697, 1991) that tracheal insufflation of 5 micrograms of TNF-alpha or 1 microgram of IL-1 markedly protects rats against O2 toxicity and enhances pulmonary Mn superoxide dismutase (Mn SOD) activity. We now report that TNF-alpha and IL-1 at subprotective doses, e.g., 1 and 0.2 micrograms, respectively, act synergistically in protecting rats against O2 toxicity. Likewise, TNF-alpha and IL-1 at 0.005 microgram/ml each act synergistically in enhancing endothelial cell Mn SOD, but not Cu,Zn SOD mRNA levels. IL-6 at 5 or 10 micrograms provides no protective effect in rats against O2 toxicity and at up to 0.5 microgram/ml has no apparent effect on endothelial cell Mn or Cu,Zn SOD mRNA levels. However, IL-6 markedly enhances TNF-alpha- and IL-1-induced increases in Mn SOD mRNA levels and O2 tolerance. These results support an important role of Mn SOD in the protection against O2 toxicity.

Colchicine has opposite effects on interleukin-1 beta and tumor necrosis factor-alpha production

1991 ◽  
Vol 261 (4) ◽  
pp. L315-L321 ◽  
Author(s):  
J. N. Allen ◽  
D. J. Herzyk ◽  
M. D. Wewers
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Cytokine Production ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Interleukin 1 Beta ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Necrosis Factor

To study the role of microtubules in cytokine production, the effect of the microtubule depolymerizing agent colchicine on lipopolysaccharide endotoxin (LPS)-induced interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) release by blood monocytes and alveolar macrophages were examined. Immunofluorescence microscopy demonstrated that LPS resulted in the appearance of microtubule-containing cytoplasmic appendages and that colchicine, which resulted in microtubule disruption in monocytes, blocked appendage formation. Colchicine resulted in approximately 50% increase in LPS-induced IL-1 beta release and a 50% decrease in LPS-induced TNF-alpha release by human monocytes at all doses of LPS tested. Although colchicine resulted in a statistically significant increase in LPS-stimulated human alveolar macrophage IL-1 beta release, the increase was not as great as that observed with monocytes. Northern blot analysis suggested that the colchicine effect occurs pretranslationally because colchicine caused an increase in LPS-stimulated IL-1 beta mRNA levels and a decrease in TNF-alpha mRNA levels. These results suggest that microtubules contribute to the regulation of endotoxin-stimulated mononuclear phagocyte cytokine production and that this regulation differs significantly between IL-1 beta and TNF-alpha.

Erythropoietin gene expression is suppressed after lipopolysaccharide or interleukin-1 beta injections in rats

1997 ◽  
Vol 273 (3) ◽  
pp. R1067-R1071 ◽  
Author(s):  
S. Frede ◽  
J. Fandrey ◽  
H. Pagel ◽  
T. Hellwig ◽  
W. Jelkmann
Keyword(s):  
Gene Expression ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Hypoxia Exposure ◽  
Factor Alpha

Proinflammatory cytokines play an important role in the pathogenesis of anemia in inflammatory diseases. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) have been reported to inhibit the synthesis of erythropoietin (EPO) in vitro. To evaluate the in vivo significance of this observation, we have investigated effects of the administration of bacterial lipopolysaccharide (LPS) and IL-1 beta on renal EPO production in rats. Measurements by competitive reverse-transcription polymerase chain reaction showed that EPO mRNA levels were significantly reduced in the kidneys of normoxic rats 6 h after the injection of LPS (0.1 or 1 mg/kg). In addition, LPS and IL-1 beta (1 microgram/kg) inhibited the increase in EPO mRNA and plasma EPO levels when administered to rats before hypoxia exposure (8% O2 in the inspiratory gas). Evidence for an inflammatory reaction in the kidneys of LPS-treated rats was provided by measurements of greatly elevated renal TNF-alpha mRNA levels. Furthermore, kidneys isolated from LPS-created rats produced less immunoreactive EPO when perfused hypoxically in vitro for 2 h. Thus mediators of the immune response inhibit renal EPO gene expression in vivo, which is relevant with respect to the impaired synthesis of EPO in inflammatory diseases in humans.

IL-1ra suppresses endotoxin-induced IL-1 beta and TNF-alpha release from mononuclear phagocytes

1994 ◽  
Vol 267 (1) ◽  
pp. L39-L45 ◽  
Author(s):  
C. B. Marsh ◽  
S. A. Moore ◽  
H. A. Pope ◽  
M. D. Wewers
Keyword(s):  
Alveolar Macrophages ◽  
Mononuclear Cells ◽  
Interleukin 1 ◽  
T Test ◽  
Mononuclear Phagocytes ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Paired T Test

The proinflammatory effects of lipopolysaccharide (LPS) are modulated in large part through the induction of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) release by mononuclear phagocytes. However, IL-1's target cell effects can be suppressed by IL-1 receptor agonist (IL-1ra). Because mononuclear phagocytes produce and respond to IL-1 via IL-1 receptors, we hypothesized that IL-1ra may also be able to block receptors on IL-1 producer cells and inhibit secondary IL-1-induced IL-1 production. To test this hypothesis, mononuclear cells and alveolar macrophages were stimulated with LPS in the presence of IL-1ra and analyzed for IL-1 beta and TNF-alpha production. For mononuclear cells, IL-1ra inhibited 6-h LPS- and IL-1 alpha-induced IL-1 beta release to 66 +/- 4% (P = 0.001 by paired t test) and 39 +/- 7% (P = 0.0005 by paired t test) of control, respectively. In addition, IL-1ra reduced both LPS- and IL-1 alpha-stimulated IL-1 beta mRNA levels to 78 and 37% of control, respectively. Furthermore, IL-1ra downregulated both LPS and IL-1 alpha-induced TNF-alpha release to 84 +/- 4% (P = 0.012 by paired t test) and 49 +/- 9% (P = 0.001 by paired t test) of control, respectively. Alveolar macrophages demonstrated variable IL-1ra-induced suppression of LPS-stimulated IL-1 beta and TNF-alpha release.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Lipopolysaccharides prime whole human blood and isolated neutrophils for the increased synthesis of 5-lipoxygenase products by enhancing arachidonic acid availability: involvement of the CD14 antigen.

1993 ◽  
Vol 178 (4) ◽  
pp. 1347-1355 ◽  
Author(s):  
M E Surette ◽  
R Palmantier ◽  
J Gosselin ◽  
P Borgeat
Keyword(s):  
Arachidonic Acid ◽  
Mononuclear Cells ◽  
Leukotriene B4 ◽  
Eicosatetraenoic Acid ◽  
Tnf Alpha ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Priming Activity

Stimulation of heparinized blood with 1 microM formyl-methionyl-leucyl-phenylalanine (FMLP) resulted in the formation of < 30 pmol/ml plasma of 5-lipoxygenase (5-LO) products. The preincubation of blood with 1 microgram/ml of lipopolysaccharide (LPS) (Escherichia coli 0111-B4) for 30 min before stimulation with FMLP resulted in the accumulation of 250-300 pmol of 5-LO products per ml plasma. The major products detected were leukotriene B4 and (5S)-hydroxy-6,8,11,14-eicosatetraenoic acid which were produced in equivalent amounts. The priming activity was detectable with as little as 1-10 ng LPS per ml blood and was optimal using 1-10 micrograms LPS/ml blood. The priming for 5-LO product synthesis was optimal after 20-30 min of preincubation with LPS and declined at preincubation times > 30 min. The priming effect of LPS was also observed using the complement fragment C5a or interleukin 8 as agonists. Polymorphonuclear leukocytes (PMN) and peripheral blood mononuclear cells accounted for 80 and 20% of the synthesis of 5-LO products, respectively. The ability of LPS to prime isolated PMN was dependent on the presence of plasma and was inhibited by the anti-CD14 antibody IOM2, indicating a CD14-dependent priming mechanism. The priming of whole blood with tumor necrosis factor alpha (TNF-alpha) and LPS was additive and the presence of mononuclear cells did not enhance the ability of LPS to prime PMN, indicating that the priming activity of LPS is independent of LPS-induced TNF-alpha synthesis. The mechanism by which LPS enhance 5-LO product synthesis in PMN was investigated. Treatment of PMN with LPS strongly enhanced the release of arachidonic acid after stimulation with FMLP. The release of arachidonic acid was optimal 2-3 min after stimulation with FMLP, attaining levels 5-15-fold greater than those observed in unprimed cells stimulated with FMLP. These results demonstrate that LPS dramatically increases the ability of blood to generate 5-LO products, and support the putative role of leukotrienes in pathological states involving LPS.

The mitogenic response to tumor necrosis factor alpha requires c-Jun/AP-1

1993 ◽  
Vol 13 (7) ◽  
pp. 4284-4290
Author(s):  
M A Brach ◽  
H J Gruss ◽  
C Sott ◽  
F Herrmann
Keyword(s):  
Tumor Necrosis ◽  
Growth Stimulation ◽  
Myelogenous Leukemia ◽  
Tnf Alpha ◽  
Mitogenic Response ◽  
Necrosis Factor Alpha ◽  
Acute Myelogenous ◽  
Factor Alpha ◽  
Necrosis Factor

In the present study, we addressed the role of the c-jun proto-oncogene in the mitogenic response of human fibroblasts and primary acute myelogenous leukemia blasts to tumor necrosis factor alpha (TNF-alpha). Our data indicate that TNF-alpha treatment of these cells is associated with transcriptional activation of c-jun, resulting in accumulation of c-jun mRNA and protein expression. In order to elucidate the role of c-Jun/AP-1 in TNF-mediated growth stimulation, the antisense (AS) technique was used. Uptake studies of oligonucleotides were performed with fibroblasts, demonstrating that incorporation of oligomers was maximal at 4 h. Oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of fibroblasts with the AS oligonucleotide resulted in intracellular duplex formation followed by an efficient translation blockade of c-Jun/AP-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and also did not interfere with translation of c-Jun/AP-1, suggesting specific elimination of c-Jun/AP-1 by the AS oligomer. Fibroblasts cultured in the presence of the AS oligonucleotide but not those cultured in the presence of the S or NS oligonucleotide failed to respond proliferatively to TNF-alpha. These findings could be confirmed by experiments with primary acute myelogenous leukemia blasts, which also demonstrated that TNF-induced growth stimulation required c-Jun/AP-1 function. Taken together, our results indicate that activation of c-Jun/AP-1 plays a pivotal role in the signaling cascade initiated by TNF, which leads to a proliferative response of its target cells.

NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1

1994 ◽  
Vol 14 (10) ◽  
pp. 6561-6569
Author(s):  
L Klampfer ◽  
T H Lee ◽  
W Hsu ◽  
J Vilcek ◽  
S Chen-Kiang
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Normal Human ◽  
Factor Alpha ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

scholarly journals Epac1 and Glycyrrhizin Both Inhibit HMGB1 Levels to Reduce Diabetes-Induced Neuronal and Vascular Damage in the Mouse Retina

2019 ◽  
Vol 8 (6) ◽  
pp. 772 ◽  
Author(s):  
Li Liu ◽  
Youde Jiang ◽  
Jena J. Steinle
Keyword(s):  
Inflammatory Mediators ◽  
Knockout Mice ◽  
Interleukin 1 ◽  
High Mobility ◽  
Sirtuin 1 ◽  
Mouse Retina ◽  
Necrosis Factor Alpha ◽  
Diabetic Retina ◽  
Factor Alpha

The role of high mobility group box 1 (HMGB1) in acute diabetic retinal damage has been demonstrated. We recently reported that glycyrrhizin, a HMGB1 inhibitor, protected the diabetic retina against neuronal, vascular, and permeability changes. In this study, we wanted to investigate the role of exchange protein for cAMP 1 (Epac1) on HMGB1 and the actions of glycyrrhizin. Using endothelial cell specific knockout mice for Epac1, we made some mice diabetic using streptozotocin, and treated some with glycyrrhizin for up to 6 months. We measured permeability, neuronal, and vascular changes in the Epac1 floxed and knockout mice. We also investigated whether Epac1 and glycyrrhizin work synergistically to reduce the retinal inflammatory mediators, tumor necrosis factor alpha (TNFα) and interleukin-1-beta (IL1β), as well as sirtuin 1 (SIRT1) levels. Epac1 and glycyrrhizin reduced inflammatory mediators with synergistic actions. Glycyrrhizin also increased SIRT1 levels in the Epac1 mice. Overall, these studies demonstrate that glycyrrhizin and Epac1 can work together to protect the retina. Finally, glycyrrhizin may regulate HMGB1 through increased SIRT1 actions.

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