Low-grade inflammation is constitutive of atherosclerosis, and anti-inflammatory therapy inhibiting interleukin-1β (IL-1β) reduces the rate of cardiovascular events. While cholesterol accumulation in atheroma plaque and macrophages is a major driver of the inflammatory process, the role of the LXR cholesterol sensors remains to be clarified. Murine and human macrophages were treated with LXR agonists for 48 h before Toll-like receptor (TLR) stimulation. Unexpectedly, we observe that, among other cytokines, LXR agonists selectively increase IL1B mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by activation of HIF-1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis. Treatment of human macrophages with carotid plaque homogenates also leads to induction of IL1B in an LXR-dependent manner. Thus, our work discloses a mechanism by which cholesterol and oxysterols trigger inflammation in atherosclerosis. This suggests perspectives to target IL-1β production in atherosclerotic patients.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Asthma is a heterogeneous disease characterized by chronic airway inflammation. It has been demonstrated that metformin, an extensively used drug for the treatment of type 2 diabetes, improves airway inflammation and remodeling. However, the mechanism by which this occurs remains poorly understood. The present study investigated the protective effects of metformin in lipopolysaccharide (LPS)‑induced human bronchial epithelial (16HBE) cells injury and the associated mechanisms. 16HBE cells were preincubated with metformin for 1 h and subsequently exposed to LPS for 12 h. A lactate dehydrogenase (LDH) leakage assay was used to determine the extent of injury to 16HBE cells. The expression of tumor necrosis factor‑α (TNF‑α) and interleukin‑6 (IL‑6) was measured by ELISA. The protein expression of intercellular adhesion molecule‑1 (ICAM‑1) and vascular cell adhesion molecule‑1 (VCAM‑1), as well as proteins associated with nuclear factor (NF)‑κB signaling, was measured by western blotting. Immunofluorescence assays confirmed the nuclear translocation of NF‑κB p65. The LDH leakage assays suggested that metformin significantly reduced LPS‑induced 16HBE cell injury. Furthermore, it was confirmed that metformin suppressed the LPS‑induced secretion of TNF‑α, IL‑6, ICAM‑1 and VCAM‑1. The mechanism occurred at least partially via inhibition of NF‑κB signaling. The results demonstrated that metformin inhibited NF‑κB mRNA expression and the nuclear translocation of NF‑κB p65. To the best of our knowledge, the present study was the first to demonstrate that metformin ameliorated LPS‑induced bronchial epithelial cell injury via NF‑κB signaling suppression.