Phosphatidylinositol 3-kinase interacts with the glucocorticoid receptor upon TLR2 activation

Arancibia, Sergio; Benitez, Dixan A.; Núñez, Lucı́a; Jewell, Christine M.; Langjahr, Patricia; Candia, Enzo; Zapata‐Torres, Gerald; Cidlowski, John A.; González, María-Julieta; Hermoso, Marcela A.

doi:10.1111/j.1582-4934.2009.00958.x

Cited by 21 publications

(20 citation statements)

References 45 publications

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“…In many cell types, GRs profoundly induce MKP-1 expression, thus attenuating the activation of MAPKs. To address the mechanism by which GRs induce MKP-1, a very recent study has indicated that GRs directly interact with PI3K to impede the phosphorylation of AKT (58). Consistently, our data also indicate that treatment of cells with DEX attenuates the activation of PI3K/Akt by LPS.…”

Section: Discussionsupporting

confidence: 77%

MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages

Zhu

Liu

Chen

et al. 2010

The Journal of Immunology

136

105

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MAPK phosphatase-1 (MKP-1) is an archetypical member of the dual-specificity phosphatase family that deactivates MAPKs. Induction of MKP-1 has been implicated in attenuating the LPS- or peptidoglycan-induced biosynthesis of proinflammatory cytokines, but the role of noncoding RNA in the expression of the MKP-1 is still poorly understood. In this study, we show that MKP-1 is a direct target of microRNA-101 (miR-101). Transfection of miR-101 attenuates induction of MKP-1 by LPS as well as prolonged activation of p38 and JNK/stress-activated protein kinase, whereas inhibition of miR-101 enhances the expression of MKP-1 and shortens p38 and JNK activation. We also found that expression of miR-101 is induced by multiple TLR ligands, including LPS, peptidoglycan, or polyinosinic-polycytidylic acid, and that inhibition of PI3K/Akt by LY294002 or Akt RNA interference blocks the induction of miR-101 by LPS in RAW264.7 macrophage cells. Moreover, treatment of cells with dexamethasone, a widely used anti-inflammatory agent, markedly inhibits miR-101 expression and enhances the expression of MKP-1 in LPS-stimulated macrophages. Together, these results indicate that miR-101 regulates the innate immune responses of macrophages to LPS through targeting MKP-1.

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Section: Discussionsupporting

confidence: 77%

MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages

Zhu

Liu

Chen

et al. 2010

The Journal of Immunology

136

105

View full text Add to dashboard Cite

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“…In this case, GCs exert non-genomic action to regulate protein metabolism by antagonizing insulin/IGF-1 responses. The interaction between GR and Pik3r1 proteins has been reported in other cell types (Arancibia et al, 2011; Hafezi-Moghadam et al, 2002; Leis et al, 2004). Identifying GR mutants that do not interact with Pik3r1 or Pik3r1 mutants which do not associate with GR will help dissect the mechanism of GC-regulated protein metabolism.…”

Section: The Regulation Of Protein Metabolism By Glucocorticoidsmentioning

confidence: 63%

Metabolic functions of glucocorticoid receptor in skeletal muscle

Kuo

Harris

Wang

2013

Molecular and Cellular Endocrinology

184

144

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Glucocorticoids (GCs) exert key metabolic influences on skeletal muscle. GCs increase protein degradation and decrease protein synthesis. The released amino acids are mobilized from skeletal muscle to liver, where they serve as substrates for hepatic gluconeogenesis. This metabolic response is critical for mammals’ survival under stressful conditions, such as fasting and starvation. GCs suppress insulin-stimulated glucose uptake and utilization and glycogen synthesis, and play a permissive role for catecholamine-induced glycogenolysis, thus preserving the level of circulating glucose, the major energy source for the brain. However, chronic or excess exposure of GCs can induce muscle atrophy and insulin resistance. GCs convey their signal mainly through the intracellular glucocorticoid receptor (GR). While GR can act through different mechanisms, one of its major actions is to regulate the transcription of its primary target genes through genomic glucocorticoid response elements (GREs) by directly binding to DNA or tethering onto other DNA-binding transcription factors. These GR primary targets trigger physiological and pathological responses of GCs. Much progress has been made to understand how GCs regulate protein and glucose metabolism. In this review, we will discuss how GR primary target genes confer metabolic functions of GCs, and the mechanisms governing the transcriptional regulation of these targets. Comprehending these processes not only contributes to the fundamental understanding of mammalian physiology, but also will provide invaluable insight for improved GC therapeutics.

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“…PI3K physically interacts with the glucocorticoid receptor (GR) through two consensus YxxM binding motifs within the GR. 21 In human fibroblasts, DXM protects cells from apoptosis via activation of PKB/Akt. 22 DXM may enhance Akt activation by low doses of EH, thus playing a synergistic role in the expression of IL-10 while remaining a strong inhibitor of proinflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

Zheng

Yang

et al. 2013

Cell Mol Immunol

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Approaches for controlling inflammatory responses and reducing the mortality rate of septic patients remain clinically ineffective; new drugs need to be identified that can induce anti-inflammatory responses. Ephedrine hydrochloride (EH) is a compound that is widely used in cardiovascular diseases, especially to treat hypotension caused by either anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of the inflammatory response. EH increased IL-10 and decreased proinflammatory cytokine (IL-6, tumor-necrosis factor (TNF)-a, IL-12 and IL-1b) expression in primary peritoneal macrophages and Raw264.7 cells treated with peptidoglycan (PGN), a Gram-positive cell wall component. The anti-inflammatory role of EH was also demonstrated in an experimental mouse model of peritonitis induced by intraperitoneal PGN injection. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for the EH-mediated increase in IL-10 production and decrease in IL-6 expression. Therefore, our results illustrated that EH can help maintain immune equilibrium and diminish host damage by balancing the production of pro-and anti-inflammatory cytokines after PGN challenge. EH may be a new potential anti-inflammatory drug that can be useful for treating severe invasive Gram-positive bacterial infection.

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Phosphatidylinositol 3-kinase interacts with the glucocorticoid receptor upon TLR2 activation

Cited by 21 publications

References 45 publications

MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages

MicroRNA-101 Targets MAPK Phosphatase-1 To Regulate the Activation of MAPKs in Macrophages

Metabolic functions of glucocorticoid receptor in skeletal muscle

Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

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