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

Abstract

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, Pam 3 Cys-Ser-(Lys) 4 (PAM). Incubation of PAM-or LPS-stimulated neutrophils with rapamycin inhibited expression of TNF-a and IL-6, but not IkB-a degradation or nuclear translocation of NF-kB. Exposure of PAM or LPS-stimulated neutrophils to rapamycin inhibited phosphorylation of serine 276 in the NF-kB p65 subunit, a phosphorylation event required for optimal transcriptional activity of NF-kB. 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-a 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.

Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice

“…Rapamycin also reverses congenital hypertrophic cardiomyopathy in juvenile mice manifesting LEOPARD syndrome (29). Furthermore, TLR4-or TLR2-induced neutrophil activation and lung injury resulting from increased mTORC1 signaling is attenuated by rapamycin treatment (30). It is interesting to note that inflammatory signals resulting from TLR4 or TRL2 activation is a potential cause of preterm birth (31).…”

A central role for the mammalian target of rapamycin in LPS-induced anorexia in mice

“…It has also been reported that inhibition of mTOR decreases the production of proinflammatory cytokines, inhibits the phosphorylation of the NFkB p65 subunit, and attenuates acute lung injury after intratracheal LPS administration (Lorne et al 2009). A previous report has shown that inhibition of NFkB attenuated the reductions in body weight and food intake induced by tumors (Kawamura et al 1999).…”

Effect of rapamycin on early stage apoptosis of neutrophils in Sprague-Dawley rats with acute lung injury

“…It has been reported that rapamycin decreased the severity of lung injury after intratracheal LPS or PAM administration, as determined by diminished neutrophil accumulation in the lungs and reduced interstitial pulmonary edema (18). The downregulation of autophagy may lead to systemic inflammation and ALI following sepsis.…”