PMID- 22025552
OWN - NLM
STAT- MEDLINE
DCOM- 20120113
LR  - 20211203
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 187
IP  - 11
DP  - 2011 Dec 1
TI  - Mammalian target of rapamycin inhibition in macrophages of asymptomatic HIV+ 
      persons reverses the decrease in TLR-4-mediated TNF-alpha release through 
      prolongation of MAPK pathway activation.
PG  - 6052-8
LID - 10.4049/jimmunol.1101532 [doi]
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-alpha 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-alpha release, but suppressed anti-inflammatory IL-10 release. Targeted gene 
      silencing of mTOR in macrophages resulted in LA-induced TNF-alpha 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-alpha release, whereas IL-10 release was inhibited in 
      both silenced and nonsilenced HIV(+) macrophages. Furthermore, mTOR inhibition 
      augmented LA-induced TNF-alpha 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-alpha 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.
FAU - Li, Xin
AU  - Li X
AD  - Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, 
      Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 
      02215, USA.
FAU - Han, Xinbing
AU  - Han X
FAU - Llano, Juliana
AU  - Llano J
FAU - Bole, Medhavi
AU  - Bole M
FAU - Zhou, Xiuqin
AU  - Zhou X
FAU - Swan, Katharine
AU  - Swan K
FAU - Anandaiah, Asha
AU  - Anandaiah A
FAU - Nelson, Benjamin
AU  - Nelson B
FAU - Patel, Naimish R
AU  - Patel NR
FAU - Reinach, Peter S
AU  - Reinach PS
FAU - Koziel, Henry
AU  - Koziel H
FAU - Tachado, Souvenir D
AU  - Tachado SD
LA  - eng
GR  - R01 HL092811/HL/NHLBI NIH HHS/United States
GR  - R01 HL092811-02/HL/NHLBI NIH HHS/United States
GR  - R01-HL063655/HL/NHLBI NIH HHS/United States
GR  - R01-HL092811/HL/NHLBI NIH HHS/United States
GR  - R01 HL063655/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111024
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Blotting, Western
MH  - Enzyme Activation/immunology
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Gene Knockdown Techniques
MH  - HIV Infections/immunology/*metabolism
MH  - Humans
MH  - Immunoprecipitation
MH  - MAP Kinase Signaling System/*immunology
MH  - Macrophages/immunology/*metabolism/virology
MH  - TOR Serine-Threonine Kinases/immunology/*metabolism
MH  - Toll-Like Receptor 4/immunology/metabolism
MH  - Tumor Necrosis Factor-alpha/immunology/*metabolism
PMC - PMC3221743
MID - NIHMS328658
EDAT- 2011/10/26 06:00
MHDA- 2012/01/14 06:00
PMCR- 2012/12/01
CRDT- 2011/10/26 06:00
PHST- 2011/10/26 06:00 [entrez]
PHST- 2011/10/26 06:00 [pubmed]
PHST- 2012/01/14 06:00 [medline]
PHST- 2012/12/01 00:00 [pmc-release]
AID - jimmunol.1101532 [pii]
AID - 10.4049/jimmunol.1101532 [doi]
PST - ppublish
SO  - J Immunol. 2011 Dec 1;187(11):6052-8. doi: 10.4049/jimmunol.1101532. Epub 2011 
      Oct 24.