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Inhibition of Mammalian Target of Rapamycin Augments Lipopolysaccharide-Induced Lung Injury and Apoptosis.
- Source :
-
Journal of Immunology . 5/1/2012, Vol. 188 Issue 9, p4535-4542. 8p. - Publication Year :
- 2012
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Abstract
- Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-&kgr;B . Ligation of TLR4 also initiates a proapoptotic response by activating IFN-β and STATl-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STATl-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STATl-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase- 3). LPS-induced lung injury was attenuated in STAT1 knockout mice. In addition, LPS and IFN-β-induced apoptosis was absent in cultured cells lacking STAT1, and, unlike in wild-type cells, a permissive effect of rapamycin was not observed. In contrast to its effect on STAT1, rapamycin inhibited NF-&kgr;B activation in vivo and reduced selected markers of inflammation (i.e., neutrophils in the bronchoalveolar lavage fluid, TNF-α). Therefore, although it inhibits NF-&kgr;B and neutrophilic inflammation, rapamycin augments LPS-induced lung injury and apoptosis in a mechanism that involves STAT1 and the induction of STATl-dependent apoptosis genes. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00221767
- Volume :
- 188
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- Journal of Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 77344597
- Full Text :
- https://doi.org/10.4049/jimmunol.1003655