Gene interactions and pathways from curated databases and text-mining
J Immunol 2011, PMID: 22025552

Mammalian target of rapamycin inhibition in macrophages of asymptomatic HIV+ persons reverses the decrease in TLR-4-mediated TNF-α release through prolongation of MAPK pathway activation.

Li, Xin; Han, Xinbing; Llano, Juliana; Bole, Medhavi; Zhou, Xiuqin; Swan, Katharine; Anandaiah, Asha; Nelson, Benjamin; Patel, Naimish R; Reinach, Peter S; Koziel, Henry; Tachado, Souvenir D

TLR-4-mediated signaling is significantly impaired in macrophages from HIV(+) persons, predominantly owing to altered MyD88-dependent pathway signaling caused in part by constitutive activation of PI3K. In this study we assessed in these macrophages if the blunted increase in TLR-4-mediated TNF-α release induced by lipid A (LA) is associated with PI3K-induced upregulation of mammalian target of rapamycin (mTOR) activity. mTOR inhibition with rapamycin enhanced TLR-4-mediated TNF-α release, but suppressed anti-inflammatory IL-10 release. Targeted gene silencing of mTOR in macrophages resulted in LA-induced TNF-α and IL-10 release patterns similar to those induced by rapamycin. Rapamycin restored MyD88/IL-1R-associated kinase interaction in a dose-dependent manner. Targeted gene silencing of MyD88 (short hairpin RNA) and mTOR (RNA interference) inhibition resulted in TLR-4-mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-α release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV(+) macrophages. Furthermore, mTOR inhibition augmented LA-induced TNF-α release through enhanced and prolonged phosphorylation of ERK1/2 and JNK1/2 MAPK, which was associated with time-dependent MKP-1 destabilization. Taken together, impaired TLR-4-mediated TNF-α release in HIV(+) macrophages is attributable in part to mTOR activation by constitutive PI3K expression in a MyD88-dependent signaling pathway. These changes result in MAPK phosphatase 1 stabilization, which shortens and blunts MAPK activation. mTOR inhibition may serve as a potential therapeutic target to upregulate macrophage innate immune host defense responsiveness in HIV(+) persons.

Diseases/Pathways annotated by Medline MESH: HIV Infections, MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

TNF-a → TLR-4: " Mammalian target of rapamycin inhibition in macrophages of asymptomatic HIV+ persons reverses the decrease in TLR-4 mediated TNF-a release through prolongation of MAPK pathway activation "

TNF-a → TLR-4: " In this study we assessed in these macrophages if the blunted increase in TLR-4 mediated TNF-a release induced by lipid A ( LA ) is associated with PI3K induced upregulation of mammalian target of rapamycin (mTOR) activity "

mammalian target of rapamycin (mTOR) → PI3K: " In this study we assessed in these macrophages if the blunted increase in TLR-4 mediated TNF-a release induced by lipid A ( LA ) is associated with PI3K induced upregulation of mammalian target of rapamycin (mTOR) activity "

TNF-a → TLR-4: " mTOR inhibition with rapamycin enhanced TLR-4 mediated TNF-a release, but suppressed anti-inflammatory IL-10 release "

ribosomal protein S6 ⊣ mTOR: " Targeted gene silencing of MyD88 ( short hairpin RNA ) and mTOR ( RNA interference ) inhibition resulted in TLR-4 mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-a release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV ( + ) macrophages "

ribosomal protein S6 ⊣ MyD88: " Targeted gene silencing of MyD88 ( short hairpin RNA ) and mTOR ( RNA interference ) inhibition resulted in TLR-4 mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-a release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV ( + ) macrophages "

TNF-a ⊣ mTOR: " Targeted gene silencing of MyD88 ( short hairpin RNA ) and mTOR ( RNA interference ) inhibition resulted in TLR-4 mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-a release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV ( + ) macrophages "

TNF-a ⊣ MyD88: " Targeted gene silencing of MyD88 ( short hairpin RNA ) and mTOR ( RNA interference ) inhibition resulted in TLR-4 mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-a release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV ( + ) macrophages "

ribosomal protein S6 → TLR-4: " Targeted gene silencing of MyD88 ( short hairpin RNA ) and mTOR ( RNA interference ) inhibition resulted in TLR-4 mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-a release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV ( + ) macrophages "

TNF-a → TLR-4: " Targeted gene silencing of MyD88 ( short hairpin RNA ) and mTOR ( RNA interference ) inhibition resulted in TLR-4 mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-a release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV ( + ) macrophages "

TNF-a ⊣ mTOR: " Furthermore, mTOR inhibition augmented LA-induced TNF-a release through enhanced and prolonged phosphorylation of ERK1/2 and JNK1/2 MAPK, which was associated with time dependent MKP-1 destabilization "

Manually curated Databases

No curated data.