This Article Full Text Full Text (PDF) All Versions of this Article: 2008-0290OCv1 41/2/237    most recent Alert me when this article is cited Alert me if a correction is posted Services Related articles in AJRCMB Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lorne, E. Articles by Abraham, E. Search for Related Content PubMed PubMed Citation Articles by Lorne, E. Articles by Abraham, E.

Participation of Mammalian Target of Rapamycin Complex 1 in Toll-Like Receptor 2– and 4–Induced Neutrophil Activation and Acute Lung Injury

¹ Department of Medicine, ² Center for Free Radical Biology, University of Alabama, Birmingham, Alabama; and ³ Institut National de la Santé et de la Recherche Médicale ERI-12, ⁴ Pole Anesthésie Réanimation, Amiens, France

Correspondence and requests for reprints should be addressed to Edward Abraham, M.D., Department of Medicine, University of Alabama at Birmingham School of Medicine, BDB 420, 1530 3rd Avenue S, Birmingham, AL 35294-0012. E-mail: eabraham{at}uab.edu

mTOR complex 1 (mTORC1) plays a central role in cell growth and cellular responses to metabolic stress. Although mTORC1 has been shown to be activated after Toll-like receptor (TLR)-4 engagement, there is little information concerning the role that mTORC1 may play in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury. To examine these issues, we determined the effects of rapamycin-induced inhibition of mTORC1 on TLR2- and TLR4-induced neutrophil activation. mTORC1 was dose- and time-dependently activated in murine bone marrow neutrophils cultured with the TLR4 ligand, LPS, or the TLR2 ligand, Pam₃ Cys-Ser-(Lys)₄ (PAM). Incubation of PAM- or LPS-stimulated neutrophils with rapamycin inhibited expression of TNF- and IL-6, but not IB- degradation or nuclear translocation of NF-B. Exposure of PAM or LPS-stimulated neutrophils to rapamycin inhibited phosphorylation of serine 276 in the NF-B p65 subunit, a phosphorylation event required for optimal transcriptional activity of NF-B. Rapamycin pretreatment inhibited PAM- or LPS-induced mTORC1 activation in the lungs. Administration of rapamycin also decreased the severity of lung injury after intratracheal LPS or PAM administration, as determined by diminished neutrophil accumulation in the lungs, reduced interstitial pulmonary edema, and diminished levels of TNF- and IL-6 in bronchoalveolar lavage fluid. These results indicate that mTORC1 activation is essential in TLR2- and TLR4-induced neutrophil activation, as well as in the development and severity of acute lung injury.

Key Words: rapamycin • neutrophil • NF-B • cytokine • mTOR

CLINICAL RELEVANCE These studies show that mammalian target of rapamycin participates in Toll-like receptor (TLR) 2– and TLR4-induced neutrophil activation as well as in the development and severity of acute lung injury.

 

Related articles in AJRCMB:

Highlights of the August Issue

Kenneth B. Adler and Sadis Matalon
AJRCMB 2009 41: 125-126. [Full Text]  

This article has been cited by other articles:

				K. Page, J. R. Ledford, P. Zhou, and M. Wills-Karp A TLR2 Agonist in German Cockroach Frass Activates MMP-9 Release and Is Protective against Allergic Inflammation in Mice J. Immunol., September 1, 2009; 183(5): 3400 - 3408. [Abstract] [Full Text] [PDF]

				K. B. Adler and S. Matalon Highlights of the August Issue Am. J. Respir. Cell Mol. Biol., August 1, 2009; 41(2): 125 - 126. [Full Text] [PDF]