Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bacterial lipopolysaccharide (LPS) elicits responses by macrophages that help the body repel infections. Recent evidence indicates that phosphatidylinositol 3-kinase (PI 3-kinase) may mediate some of these responses. Here, we show that exposing macrophages to LPS rapidly increased membrane-associated PI 3-kinase activity and also elevated p70 S6 kinase activity. Inhibitors of PI 3-kinase or the mammalian target of rapamycin (mTOR) fully blocked p70 S6 kinase activation, implying that this kinase is controlled by PI 3-kinase and mTOR. These inhibitors also substantially reduced LPS-induced nitric oxide (NO) production. This inhibition was, in part, attributable to impaired LPS-stimulated secretion of interferon-beta, an autocrine co-factor for NO production. However, the addition of exogenous interferon-beta did not fully restore NO production, indicating that the NO response was being inhibited by another mechanism as well. Together, these data suggest that PI 3-kinase, mTOR, and possibly p70 S6 kinase mediate LPS-induced NO production by regulating the secretion of interferon-beta and by a second undefined mechanism.
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PMID:Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta. 1073 2

In the present study, differential responses of regulatory proteins involved in translation initiation in skeletal muscle and liver during sepsis were studied in neonatal pigs treated with lipopolysaccharide (LPS). LPS did not alter eukaryotic initiation factor (eIF) 2B activity in either tissue. In contrast, binding of eIF4G to eIF4E to form the active mRNA-binding complex was repressed in muscle and enhanced in liver. Phosphorylation of eIF4E-binding protein, 4E-BP1, and ribosomal protein S6 kinase, S6K1, was reduced in muscle during sepsis but increased in liver. Finally, changes in 4E-BP1 and S6K1 phosphorylation were associated with altered phosphorylation of the protein kinase mammalian target of rapamycin (mTOR). Overall, the results suggest that translation initiation in both skeletal muscle and liver is altered during neonatal sepsis by modulation of the mRNA-binding step through changes in mTOR activation. Moreover, the LPS-induced changes in factors that regulate translation initiation are more profound than previously reported changes in global rates of protein synthesis in the neonate. This finding suggests that the initiator methionyl-tRNA-rather than the mRNA-binding step in translation initiation may play a more critical role in maintaining protein synthesis rates in the neonate during sepsis.
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PMID:Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs. 1277 8

Mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) regulate cell growth, protein synthesis, and apoptosis in response to nutrients and mitogens. As an important source of nitric oxide during inflammation, human inducible nitric oxide synthase also plays a role in the regulation of cytokine-driven cell proliferation and apoptosis. The role of mTOR and PI3K in the activation of human inducible nitric oxide synthase transcription by cytokines and lipopolysaccharide (LPS) was investigated in lung epithelial adenocarcinoma (A549) cells. LY294002, a dual mTOR and PI3K inhibitor, blocked human inducible nitric oxide synthase (hiNOS) promoter activation and mRNA induction by cytokines and LPS in a PI3K-independent fashion. On gene expression analysis, LY294002 selectively blocked the induction of a subset of 14 LPS/interferon-gamma (IFN-gamma)-induced genes, previously characterized as signal transducer and activator of transcription-1 (STAT1)-dependent. LY294002, but not wortmannin, inhibited LPS/IFN-gamma-dependent STAT1 phosphorylation at Ser-727 and STAT1 activity. Consistent with dual inhibition of mTOR and PI3K by LY294002, dominant-negative mTOR, anti-mTOR small interfering RNA, or rapamycin each inhibited phosphorylation of STAT1 only in the presence of wortmannin. LPS/IFN-gamma led to the formation of a macromolecular complex containing mTOR, STAT1, as well as protein kinase C delta, a known STAT1alpha kinase. Thus, LPS and IFN-gamma activate the PI3K and mTOR pathways, which converge to regulate STAT1-dependent transcription of pro-apoptotic and pro-inflammatory genes in a rapamycin-insensitive manner.
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PMID:Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin. 1280 16

Macrophages are pivotal effector cells in the innate immune system. When microbial products bind to pathogen recognition receptors, macrophages are activated and release a broad array of mediators, such as cytokines, that orchestrate the inflammatory responses of the host. Phosphatidic acid (PA) has been implicated as an important metabolite of phospholipid biosynthesis and in membrane remodeling and has been further suggested to be a crucial second messenger in various cellular signaling events. Here we show that PA is an essential regulator of inflammatory response. Deleterious effects of PA are associated with the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and the production of nitric oxide, prostaglandin E2, which are predominantly released by macrophage Raw264.7 cells. Furthermore, the administration of PA to mice increased the serum cytokine level. Moreover, direct or lipopolysaccharide-induced PA accumulation by macrophages led to the Akt-dependent activation of the mammalian target of rapamycin-p70 S6 kinase 1, a process required for the induction of inflammatory mediators. These findings demonstrate the importance of the role of PA in systemic inflammatory responses, and provide a potential usefulness as specific targets for the development of therapies.
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PMID:Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway. 1296 Jan 76

Endotoxin (i.e., lipopolysaccharide, LPS) impairs skeletal muscle protein synthesis. Although this impairment is not acutely associated with a decreased plasma concentration of total amino acids, LPS may blunt the anabolic response to amino acids. To examine this hypothesis, rats were injected intraperitoneally with LPS or saline (Sal) and 4 h thereafter were orally administered either leucine (Leu) or Sal. The gastrocnemius was removed 20 min later to assess signaling components important in the translational control of protein synthesis. In the Sal-Leu group phosphorylation of 4E-BP1 in muscle was markedly increased, compared to values from time-matched saline-treated control rats. This change was associated with a redistribution of eukaryotic initiation factor (eIF) 4E from the inactive eIF4E x 4E-BP1 complex to the active eIF4E x eIF4G complex. In LPS-treated rats, the Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were partially or completely abrogated. LPS also antagonized the Leu-induced increase in phosphorylation of S6K1, ribosomal protein S6 and mTOR. Neither LPS nor leu altered the total amount or phosphorylation of TSC2 in muscle. The ability of LPS to blunt the anabolic effects of Leu could not be attributed to differences in the plasma concentrations of insulin or Leu between groups. Furthermore, the replacement of plasma insulin-like growth factor (IGF)-I in LPS-treated rats to basal levels also did not ameliorate the defect in leucine-induced phosphorylation of S6K1 or S6, although it did reverse the LPS-induced decrease in the constitutive phosphorylation of mTOR, S6 and 4E-BP1. Pretreatment with the glucocorticoid receptor antagonist RU486 was unable to prevent the LPS-induced leucine resistance. In contrast, to the abovementioned results with leucine, LPS did not prevent the ability of pharmacological levels of IGF-I to phosphorylate 4E-BP1, S6K1, mTOR or alter the availability of eIF4E. Hence, LPS working via a glucocorticoid-independent mechanism produces a leucine resistance in skeletal muscle that might be expected to impair the ability of this amino acid to stimulate translation initiation and protein synthesis.
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PMID:Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. 1538 31

Skeletal muscle demonstrates great plasticity in response to environmental and hormonal factors including pathogen-associated molecules, inflammatory cytokines, and growth factors. These signals impinge on muscle by forcing individual muscle fibers to either grow or atrophy. We recently demonstrated that skeletal muscle cells express multiple Toll-like receptors (TLR) that recognize bacterial cell wall components, such as lipopolysaccharide (LPS). Exposure of myocytes to LPS and other TLR ligands initiates an inflammatory response culminating in the autocrine production of cytokines and NO by NO synthase (NOS)2. The TLR signal through protein kinases that phosphorylate and promote the degradation of an inhibitory protein that normally retains the transcription factor, nuclear factor kappaB (NFkappaB), in the cytoplasm. Phosphorylation and degradation of the inhibitor of NFkappaB allows for translocation of NFkappaB to the nucleus and activation of inflammatory genes. Overexpression of a constitutively active inhibitor of NFkappaB kinase in skeletal muscle causes severe wasting, and we found that inhibitors of either the phosphorylation of IkappaB or its proteolytic degradation prevent TLR ligand-induced expression of cytokines and NOS2. The combination of LPS and interferon gamma dramatically enhances the magnitude and duration of LPS-stimulated NOS2 expression and reduces protein translation. Lipopolysaccharide and interferon gamma also downregulates signaling from the mammalian target of rapamycin, a kinase that directs changes in cell size. Inhibitors of NOS block the fall in muscle cell protein synthesis and restore translational signaling, indicating that activation of the NOS2-NO pathway is responsible for the observed decrease in muscle protein synthesis. Our work provides a molecular explanation for reduced muscle growth during infection. Muscle is largely self-sufficient because it expresses receptors, signaling pathways, and effectors to regulate its own size. Prolonged activation of NFkappaB and NOS2 have emerged as detrimental facets of the immune response in muscle. The interplay between inflammatory components and growth factor signaling clearly places muscle at the interface between growth and immunity.
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PMID:Regulation of muscle growth by pathogen-associated molecules. 1819 60

Phosphoinositide 3-kinase (PI3K) negatively regulates Toll-like receptor (TLR)-mediated interleukin-12 (IL-12) expression in dendritic cells (DCs). We show here that 2 signaling pathways downstream of PI3K, mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 (GSK3), differentially regulate the expression of IL-12 in lipopolysaccharide (LPS)-stimulated DCs. Rapamycin, an inhibitor of mTOR, enhanced IL-12 production in LPS-stimulated DCs, whereas the activation of mTOR by lentivirus-mediated transduction of a constitutively active form of Rheb suppressed the production of IL-12. The inhibition of protein secretion or deletion of IL-10 cancelled the effect of rapamycin, indicating that mTOR regulates IL-12 expression through an autocrine action of IL-10. In contrast, GSK3 positively regulates IL-12 production through an IL-10-independent pathway. Rapamycin-treated DCs enhanced Th1 induction in vitro compared with untreated DCs. LiCl, an inhibitor of GSK3, suppressed a Th1 response on Leishmania major infection in vivo. These results suggest that mTOR and GSK3 pathways regulate the Th1/Th2 balance though the regulation of IL-12 expression in DCs. The signaling pathway downstream of PI3K would be a good target to modulate the Th1/Th2 balance in immune responses in vivo.
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PMID:Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. 1849 54

beta-Hydroxy-beta-methylbutyrate (HMB; 50 microM) has been shown to attenuate the depression in protein synthesis in murine myotubes in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-alpha) with or without interferon-gamma (IFN-gamma), and angiotensin II (ANG II). The mechanism for the depression of protein synthesis by all three agents was the same and was attributed to activation of double-stranded RNA-dependent protein kinase (PKR) with the subsequent phosphorylation of eukaryotic initiation factor 2 (eIF2) on the alpha-subunit as well as increased phosphorylation of the elongation factor (eEF2). Myotubes expressing a catalytically inactive PKR variant, PKRDelta6, showed no depression of protein synthesis in response to either LPS or TNF-alpha, confirming the importance of PKR in this process. There was no effect of any of the agents on phosphorylation of mammalian target of rapamycin (mTOR) or initiation factor 4E-binding protein (4E-BP1), and thus no change in the amount of eIF4E bound to 4E-BP1 or the concentration of the active eIF4E.eIF4G complex. HMB attenuated phosphorylation of eEF2, possibly by increasing phosphorylation of mTOR, and also attenuated phosphorylation of eIF2alpha by preventing activation of PKR. These results suggest that HMB may be effective in attenuating muscle atrophy in a range of catabolic conditions.
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PMID:Attenuation of depression of muscle protein synthesis induced by lipopolysaccharide, tumor necrosis factor, and angiotensin II by beta-hydroxy-beta-methylbutyrate. 1885 27

Bacterial lipopolysaccharide (LPS) induces monocytes/macrophages to express proinflammatory cytokines and tissue factor (TF), the primary activator of the coagulation cascade. Anti-inflammatory signaling pathways including the phosphatidylinositol-3-kinase (PI3K)-Akt pathway inhibit proinflammatory and TF gene expression in macrophages. We determined the role of Akt, the mammalian target of rapamycin (mTOR) and interleukin-10 in the inhibition of LPS-induced proinflammatory cytokine and TF gene expression in peritoneal macrophages (PMs). We used wild type (WT) peritoneal macrophages (PMs), and PMs from PTEN(flox/flox)/LysMCre mice (PTEN(-/-) PMs), which have increased Akt activity. Pharmacologic inhibition of mTOR with rapamycin inhibited LPS induction of IL-10 mRNA and protein, and enhanced the expression of TF and the proinflammatory cytokine TNFalpha in WT PMs. Furthermore, neutralizing IL-10 with anti-IL-10 antibody enhanced LPS induction of TNFalpha and TF expression in WT PMs. The addition of recombinant IL-10 abolished rapamycin enhancement of LPS-induced TNFalpha and TF expression in WT PMs. Consistent with enhanced Akt activation, LPS-induced IL-10 expression was increased in PTEN(-/-) PMs compared to WT PMs. In contrast, LPS-induced TNFalpha and TF expression was significantly reduced in PTEN(-/-) PMs compared to WT PMs. However, the neutralizing IL-10 antibody did not completely prevent inhibition of LPS-induced TNFalpha and TF expression in PTEN(-/-) PMs. The results indicate that mTOR dependent IL-10 expression leads to inhibition of LPS induction of TF and the proinflammatory cytokine TNFalpha in WT macrophages. In contrast, the decrease in LPS-induced TNFalpha and TF expression in PTEN(-/-) PMs also requires an IL-10-independent pathway.
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PMID:Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression. 1944 94

We investigated the effect of rapamycin, a specific inhibitor of the mammalian serine/threonine kinase, mammalian target of rapamycin (mTOR), on the expression of inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Pretreatment of cells with rapamycin significantly inhibited LPS-induced nitrite production and the expression of iNOS protein in a dose-dependent manner. However, LPS-induced mRNA expression of iNOS and its concomitant activation of nuclear factor (NF)-kappaB remained unchanged by rapamycin. Intriguingly, LPS-induced nitrite production and iNOS protein expression were partially blocked at nanomolar concentrations of rapamycin, whereas phosphorylation of both p70 S6 kinase and 4E-BP1 was completely abolished. The suppression of LPS-induced iNOS expression by rapamycin was reversed by the protease inhibitor lactacystin. Furthermore, rapamycin treatment stimulated 20S proteasome activity, which was slightly elevated by LPS. Taken together, our findings strongly suggest that rapamycin down-regulates LPS-induced iNOS protein expression via proteasomal activation, as well as through inhibition of the mTOR signaling pathway.
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PMID:Rapamycin down-regulates inducible nitric oxide synthase by inducing proteasomal degradation. 1948 3


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