Rapamycin ameliorates lipopolysaccharide-induced acute lung injury by inhibiting IL-1β and IL-18 production

Abstract

Interleukin (IL)-1β and IL-18 play central and detrimental roles in the development of acute lung injury (ALI), and mammalian target of rapamycin (mTOR) is involved in regulating IL-1β and IL-18 production. However, it is not clear whether the mTOR specific inhibitor rapamycin can attenuate lipopolysaccharide (LPS)-induced ALI by modulating IL-1β and IL-18 production. In this study, we found that rapamycin ameliorated LPS-induced ALI by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1β and IL-18 secretion. Mechanistically, elevated autophagy and decreased nuclear factor (NF)-κB activation were associated with downregulated IL-1β and IL-18. Moreover, rapamycin reduced leukocyte infiltration in the lung tissue and bronchoalveolar lavage fluid (BALF), and contributed to the alleviation of LPS-induced ALI. Consistently, rapamycin also significantly inhibited IL-1β and IL-18 production by RAW264.7 cells via increased autophagy and decreased NF-κB signaling in vitro. Our results demonstrated that rapamycin protects mice against LPS-induced ALI partly by inhibiting the production and secretion of IL-1β and IL-18. mTOR and rapamycin might represent an appropriate therapeutic target and strategy for preventing ALI induced by LPS.

Keywords: Acute lung injury; Autophagy; IL-18; IL-1β; NF-κB; mTOR.