Molecular mechanisms of endotoxin tolerance

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 Gi 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-kappaB) 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-kappaB (IkappaB) isoforms. Also at the nuclear level, increase in the NF-kappaB subunit p50 homodimer expression and increased activation of peroxisome-proliferator-activated receptors-gamma (PPARgamma) 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.

Increased expression and internalization of the endotoxin coreceptor CD14 in enterocytes occur as an early event in the development of experimental necrotizing enterocolitis

“…Our current finding that TLR4 and CD14 co-localize and are co-internalized upon LPS exposure underscore this possibility. The subsequent decrease in CD14 expression and signaling may represent a state of acquired endotoxin tolerance, as has recently been described to occur in other systems (28,29).…”

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

“…Defects in TLR4 signaling have been observed at the level of the receptor, adaptors (MyD88 and TRIF) (44,45), signaling molecules, and transcription factors. Several investigators suggested that ET in human monocytes and mouse macrophages is associated with decreased TLR4-MyD88-IRAK complex formation, impairment of IRAK-1 activity, and TRAF6 expression (45)(46)(47)(48)(49). In this regard, miRNAs have emerged as an important regulatory mechanism for gene expression of a number of TLR4 pathway components during ET (49); in particular, miR146a is critical for ET development in human monocytes (48,(50)(51)(52)(53)(54).…”

Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies

“…However, 2 days after initial exposure, they no longer made TNF-a or activated the JNK or NF-kB stress signaling pathways in response to the agonist (Shi et al, 2007). These cells were said to have been 'tolerized' by analogy with TLR-activated normal monocytes (Fan and Cook, 2004). Importantly, CLL cells in the TLR-tolerized state became exquisitely sensitive to CTLs (Spaner et al, 2006) and chemotherapeutic agents (Shi et al, 2007) in vitro.…”

“…If the ability of mitochondria to make ATP via oxidative phosphorylation is inhibited (by culturing the cells in a hypoxic chamber, or using electron-transport chain inhibitors, such as Antimycin-A or oligomycin), CLL cells that have been activated with TLR7 agonists do not exhibit enhanced sensitivity to cytotoxic drugs, although they remain unable to make TNF-a, or activate JNK or NF-kB, in response to restimulation through TLR7. Accordingly, our understanding of the TLR-tolerized state (defined only as the inability to make TNF-a upon restimulation with a TLR agonist; Fan and Cook, 2004) is incomplete. The state seems to result from a cell differentiation process mediated by genes whose expression can be blocked by the transcriptional inhibitor, actinomycin D (Shi et al, 2007).…”

“…Cyclooxygenase-2 results in production of prostaglandins (PGs), such as PGE2, which have been shown to prevent TNF-a production by lipopolysaccharide-activated monocytes (Takahashi et al, 2005). Many of these gene products are implicated in the development of endotoxin tolerance in normal cells (Randow et al, 1995;Fan and Cook, 2004), but might prevent the initial strong stimulation required to tolerize tumor cells if present when a TLR agonist is injected.…”