PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice

Schabbauer, Gernot; Tencati, Michael; Pedersen, Brian; Pawliński, Rafał; Mackman, Nigel

doi:10.1161/01.atv.0000143096.15099.ce

Cited by 221 publications

(195 citation statements)

References 53 publications

(78 reference statements)

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“…PI3K and TLR signaling share several downstream signaling components (22,23,48), however, the role of PI3K in TLR4 signaling, such as LPS is controversial. Several papers (49,50) show that inhibition of PI3K leads to an increase in LPS-induced proinflammatory cytokines such TNF-␣ and tissue factor in monocytes and blood, suggesting that PI3K could be an endogenous inhibitor of LPS-induced cytokines. However, Ojaniemi et al (22) did show that TLR4 activation of IL-1␤ was dependent on PI3K activity.…”

Section: Discussionmentioning

confidence: 99%

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Sherry¹,

O’Connor²,

Kramer

et al. 2007

The Journal of Immunology

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Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-α production by resident peritoneal macrophages (PerMφ) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-α in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMφ. Ex vivo stimulation of PerMφ with LPS produced a similar 3-fold increase in TNF-α production in db/db PerMφ when compared with db/+ PerMφ. PerMφ isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-α in response to LPS than PerMφ incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMφ from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-α production in PerMφ from db/db mice. Taken together, these data indicate that augmented TNF-α production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.

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Section: Discussionmentioning

confidence: 99%

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Sherry¹,

O’Connor²,

Kramer

et al. 2007

The Journal of Immunology

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“…123,124 In endothelial cells and monocytes, inhibition of the PI3K-Akt pathway has been shown to enhance LPSinduced cytokine production, suggesting a negative regulatory role for PI3K. 125 Activation of PI3K also reduces MyD88-dependent production of the proinflammatory molecules IL-12 in dendritic cells and TNFa in monocytes. 126,127 In C6 glial cells stimulated with LPS, inhibition of PI3K results in the induction of NOS.…”

Section: Phosphatidylinositol 3-kinasementioning

confidence: 99%

Lipopolysaccharide signaling in endothelial cells

Dauphinee

Karsan

2006

Laboratory Investigation

534

433

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Sepsis is the systemic immune response to severe bacterial infection. The innate immune recognition of bacterial and viral products is mediated by a family of transmembrane receptors known as Toll-like receptors (TLRs). In endothelial cells, exposure to lipopolysaccharide (LPS), a major cell wall constituent of Gramnegative bacteria, results in endothelial activation through a receptor complex consisting of TLR4, CD14 and MD2. Recruitment of the adaptor protein myeloid differentiation factor (MyD88) initiates an MyD88-dependent pathway that culminates in the early activation of nuclear factor-jB (NF-jB) and the mitogen-activated protein kinases. In parallel, a MyD88-independent pathway results in a late-phase activation of NF-jB. The outcome is the production of various proinflammatory mediators and ultimately cellular injury, leading to the various vascular sequelae of sepsis. This review will focus on the signaling pathways initiated by LPS binding to the TLR4 receptor in endothelial cells and the coordinated regulation of this pathway.

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“…Recent studies provided evidence that PI3K regulates innate responses to microbial pathogens [16,17] and limits the production of inflammatory mediators in response to bacterial LPS [18][19][20][21][22]. PI3K was shown to regulate MyD88-dependent events [23][24][25][26] but its role in the TRIF-dependent signaling cascade has not been demonstrated so far.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

Aksoy

Berghe²,

Detienne

et al. 2005

Eur. J. Immunol.

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Phosphoinositide 3-kinases (PI3K) are known to regulate Toll-like receptor (TLR)-mediated inflammatory responses, but their impact on the different pathways of TLR signaling remains to be clarified. Here, we investigated the consequences of pharmacological inhibition of PI3K on Toll-IL-1 receptor domain-containing adapterinducing IFN-b (TRIF)-dependent signaling, which induces IFN-b gene expression downstream of TLR3 and TLR4. First, treatment of monocyte-derived dendritic cells (DC) with wortmannin or LY294002 was found to enhance IFN-b expression upon TLR3 or TLR4 engagement. In the same models of DC activation, PI3K inhibition increased DNA-binding activity of NF-jB, but not interferon response factor (IRF)-3, the key transcription factors required for TLR-mediated IFN-b synthesis. In parallel, wortmannin-treated DC exhibited enhanced levels of IjB kinase (IKK)-a/b phosphorylation and IjB-a degradation with a concomitant increase in NF-jB nuclear translocation. Experiments carried out in HEK 293T cells stably expressing TLR3 or TLR4 confirmed that inhibition of PI3K activity enhances NF-jB-dependent promoters as well as IFN-b promoter activities without interfering with transcription at the positive regulatory domain III-I. Furthermore, wortmannin enhanced NF-jB activity induced by TRIF overexpression in HEK 293T cells, while overexpression of catalytically active PI3K selectively attenuated TRIF-mediated NF-jB transcriptional activity. Finally, in coimmunoprecipitation experiments, we showed that PI3K physically interacted with TRIF. We conclude that inhibition of PI3K activity enhances TRIF-dependent NF-jB activity, and thereby increases IFN-b synthesis elicited by TLR3 or TLR4 ligands.

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PI3K-Akt Pathway Suppresses Coagulation and Inflammation in Endotoxemic Mice

Cited by 221 publications

References 53 publications

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Augmented Lipopolysaccharide-Induced TNF-α Production by Peritoneal Macrophages in Type 2 Diabetic Mice Is Dependent on Elevated Glucose and Requires p38 MAPK

Lipopolysaccharide signaling in endothelial cells

Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-κB activation and IFN-β synthesis downstream of Toll-like receptor 3 and 4

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