Role of NFkappaB in the mortality of sepsis.

Böhrer, H.; Qiu, Fu; Zimmermann, Thomas; Zhang, Y; Jllmer, T; Dn, Männel; Böttiger, Bernd W.; Stern, David M.; Waldherr, Rüdiger; Saeger, H D; Ziegler, Reinhard; Bierhaus, Angelika; Martin, Eike; Nawroth, Peter P.

doi:10.1172/jci119648

Cited by 441 publications

(296 citation statements)

References 61 publications

Supporting

Mentioning

270

Contrasting

Unclassified

Order By: Relevance

“…Of clinical relevance, NF-B binding activity was increased in patients with acute inflammation and sepsis and correlated with clinical severity and mortality (34,35). In the present study we showed that LPS induced NF-B DNA binding activity in human monocytic cells and in various tissues of mice, and LA treatment strongly suppressed NF-B activation and NF-B-dependent upregulation of CAMs, TNF␣, and MCP-1.…”

Section: Discussionsupporting

confidence: 62%

α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

Zhang

Wu²,

Hagen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

227

173

View full text Add to dashboard Cite

, heart, and aorta. Lipoic acid also improved survival of endotoxemic mice. All of these antiinflammatory effects of LA were abolished by treatment of the animals with wortmannin. We conclude that LA inhibits LPS-induced monocyte activation and acute inflammatory responses in vitro and in vivo by activating the PI3K/Akt pathway. Lipoic acid may be useful in the prevention of sepsis and inflammatory vascular diseases.inflammation ͉ NF-B ͉ sepsis ͉ endothelial activation ͉ monocytes

show abstract

Section: Discussionsupporting

confidence: 62%

α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

Zhang

Wu²,

Hagen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

227

173

View full text Add to dashboard Cite

show abstract

“…NF-B inhibitors such as epigallocatechin-3-gallate (47), ethyl pyruvate (48), and parthenolide (49) have been shown to improve survival in rodent CLP-type models of sepsis. Similarly, it was shown that fatal outcome of sepsis is associated with highly increased NF-B activity in mononuclear cells of septic patients (50,51). This outcome is not contradictory to our results.…”

Section: Nf-b and The Septic Counter-regulatory Responsesupporting

confidence: 70%

Enhancement of NF-κB Activation in Lymphocytes Prevents T Cell Apoptosis and Improves Survival in Murine Sepsis

Groesdonk

Wagner

Hoffarth

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Sepsis induces extensive lymphocyte apoptosis that contributes to immunosuppression and mortality. Activation of the canonical NF-κB pathway, however, prevents TNF-α–induced lymphocyte apoptosis. In this study the function of canonical NF-κB in T cells was studied in the context of murine sepsis. Upon cecal ligation and puncture (CLP), NF-κB DNA binding activity in thymocytes declines relative to sham-operated mice. This decline in NF-κB activity is most likely due to posttranslational modifications such as deacetylation of p65. In parallel, cleavage of procaspase-3 is increased, whereas expression of NF-κB-dependent antiapoptotic genes Bcl-xL and c-IAP2 is suppressed upon sepsis induction. Interestingly, adoptive transfer of IκBα-deficient fetal liver stem cells into sublethally irradiated lymphopenic host mice reduced the decline in thymocyte survival, increased peripheral T cell numbers, and improved the mortality rate relative to wild-type reconstituted hosts after cecal ligation and puncture. In conclusion, lymphocyte-directed augmentation of canonical NF-κB ameliorates immunosuppression during murine sepsis. These data provide evidence for a new approach in sepsis therapy.

show abstract

“…The induction occurs rapidly within 1 h and is maintained during the next 48 h. We also found a small but significant effect of FFA-free BSA alone on IL-6 gene expression. We suggest that contamination with low endotoxin amounts in the BSA preparation accounted for this induction of IL-6 because NF-B activity, known to be readily induced by endotoxins (42), is slightly enhanced in BSA-treated myotubes. The novel finding that saturated FFAs induce IL-6 expression is striking because the current view is that IL-6 expression is regulated by mediators of the pro-and anti-inflammatory network.…”

Section: Discussionmentioning

confidence: 86%

Palmitate, but Not Unsaturated Fatty Acids, Induces the Expression of Interleukin-6 in Human Myotubes through Proteasome-dependent Activation of Nuclear Factor-κB

Weigert

Brodbeck

Staiger

et al. 2004

Journal of Biological Chemistry

243

187

View full text Add to dashboard Cite

Circulating interleukin-6 (IL-6), insulin, and free fatty acid (FFA) concentrations are associated with impaired insulin action in obese and type 2 diabetic individuals. However, a causal relationship between elevated plasma FFAs and IL-6 has not been shown. Because skeletal muscle represents a major target of impaired insulin action, we studied whether FFAs may affect IL-6 expression in human myotubes. We demonstrate that specifically saturated FFAs, e.g. palmitate (0.25 mM), induce IL-6 mRNA expression and protein secretion by a proteasome-dependent mechanism that leads to a rapid and chronic activation of nuclear factor-B. Insulin, high glucose concentrations, or unsaturated FFAs did not activate IL-6 expression. In fact, the unsaturated FFA linoleate inhibited palmitate-induced IL-6 production. Because inhibition of palmitate metabolism by the acyl-CoA synthetase inhibitor triacsin C did not abolish IL-6 expression, it appears that the palmitate molecule per se exerts the observed effects. Furthermore, we show that in human myotubes, IL-6 activates the phosphorylation of signal transducer and activator of transcription 3 in concentrations similar to hepatocytes. However, no inhibitory effect of IL-6 on insulin action, determined as phosphatidylinositol 3-kinase association with insulin receptor substrate-1, Akt phosphorylation, and glycogen synthesis, was detected. We conclude that IL-6 expression may be modulated by the composition of circulating FFA, e.g. by diet, and that skeletal muscle cells could be target cells for IL-6.

show abstract

Role of NFkappaB in the mortality of sepsis.

Abstract: Binding activity for nuclear factor kappa B (NF B) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (

Cited by 441 publications

References 61 publications

α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

Enhancement of NF-κB Activation in Lymphocytes Prevents T Cell Apoptosis and Improves Survival in Murine Sepsis

Palmitate, but Not Unsaturated Fatty Acids, Induces the Expression of Interleukin-6 in Human Myotubes through Proteasome-dependent Activation of Nuclear Factor-κB

Contact Info

Product

Resources

About