Review: Molecular mechanisms of endotoxin tolerance

TLDR

Endotoxin tolerance, a state of reduced responsiveness to lipopolysaccharide, has been extensively studied but its molecular underpinnings remain unclear, with investigations focusing on TLR family receptors, cell surface molecules, signaling proteins, and cytokine mediators. Tolerance is characterized by maintained or increased expression of LBP, CD14, MD‑2, and TLR2, transient suppression of TLR4, enhanced IRAK degradation, reduced TLR4‑MyD88 signaling, diminished Gi, PKC, MAPK, AP‑1, and NF‑κB activity, and up‑regulation of anti‑inflammatory mediators such as IRAK‑M, SOCS‑1, PI3K, IκB, NF‑κB p50 homodimers, and PPARγ, reflecting a complex counter‑regulatory response.

Abstract

The phenomenon of endotoxin tolerance has been widely investigated, but to date, the molecular mechanisms of endotoxin tolerance remain to be resolved clearly. The discovery of the Toll-like receptor (TLR) family as the major receptors for lipopolysaccharide (LPS) and other bacterial products has prompted a resurgence of interest in endotoxin tolerance mechanisms. Changes of cell surface molecules, signaling proteins, pro-inflammatory and anti -inflammatory cytokines and other mediators have been examined. During tolerance expression of LPS-binding protein (LBP), CD14, myeloid differentiation protein-2 (MD-2) and TLR2 are unchanged or up-regulated, whereas TLR4 is transiently suppressed or unchanged. Proximal post-receptor signaling proteins that are altered in tolerance include augmented degradation of interleukin-1 receptor-associated kinase (IRAK), and decreased TLR4-myeloid differentiation factor 88 (MyD88) and IRAK-MyD88 association. Tolerance has also been shown to be associated with decreased G i protein content and activity, decreased protein kinase C (PKC) activity, reduction in mitogen-activated protein kinase (MAP kinase) activity, and reduced activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB) induced gene transactivation. However, not all signaling proteins and pathways are suppressed in tolerance and induction of specific anti-inflammatory proteins and signaling pathways may serve important counter inflammatory functions. The latter include induction of IRAK-M and suppressor of cytokine-signaling-1 (SOCS-1), phosphoinositide-3-kinase (PI3K) signaling, and increased or maintained expression of inhibitor-κB (IκB) isoforms. Also at the nuclear level, increase in the NFκB subunit p50 homodimer expression and increased activation of peroxisome-proliferatoractivated receptors-γ (PPARγ) have been linked to tolerance phenotype. Although there are species and cellular variations in manifestation of the LPS tolerant phenotype, it is clear that the tolerance phenomena have evolved as a complex orchestrated counter regulatory response to inflammation.