RT Journal Article
SR Electronic
T1 Mammalian Target of Rapamycin Inhibition in Macrophages of Asymptomatic HIV<sup>+</sup> Persons Reverses the Decrease in TLR-4–Mediated TNF-α Release through Prolongation of MAPK Pathway Activation
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 6052
OP 6058
DO 10.4049/jimmunol.1101532
VO 187
IS 11
A1 Li, Xin
A1 Han, Xinbing
A1 Llano, Juliana
A1 Bole, Medhavi
A1 Zhou, Xiuqin
A1 Swan, Katharine
A1 Anandaiah, Asha
A1 Nelson, Benjamin
A1 Patel, Naimish R.
A1 Reinach, Peter S.
A1 Koziel, Henry
A1 Tachado, Souvenir D.
YR 2011
UL http://www.jimmunol.org/content/187/11/6052.abstract
AB 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.