Elevated pre-activation basal level of nuclear NF-?B in native macrophages accelerates LPS-induced translocation of cytosolic NF-?B into the cell nucleus.

ABSTRACT: Signaling via Toll-like receptor 4 (TLR4) in macrophages constitutes an essential part of the innate immune response to bacterial infections. Detailed and quantified descriptions of TLR4 signal transduction would help to understand and exploit the first-line response of innate immune defense. To date, most mathematical modelling studies were performed on transformed cell lines. However, properties of primary macrophages differ significantly. We therefore studied TLR4-dependent activation of NF-?B transcription factor in bone marrow-derived and peritoneal primary macrophages. We demonstrate that the kinetics of NF-?B phosphorylation and nuclear translocation induced by a wide range of bacterial lipopolysaccharide (LPS) concentrations in primary macrophages is much faster than previously reported for macrophage cell lines. We used a comprehensive combination of experiments and mathematical modeling to understand the mechanisms of this rapid response. We found that elevated basal NF-?B in the nuclei of primary macrophages is a mechanism increasing native macrophage sensitivity and response speed to the infection. Such pre-activated state of macrophages accelerates the NF-?B translocation kinetics in response to low agonist concentrations. These findings enabled us to refine and construct a new model combining both NF-?B phosphorylation and translocation processes and predict the existence of a negative feedback loop inactivating phosphorylated NF-?B.

SUBMITTER: Bagaev AV 

PROVIDER: S-EPMC6418260 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature