Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock.

摘要: Background  Early murine endotoxin-induced ileus at 6 h is exclusively mediated by non-hemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role in LPS/TLR4-triggered and inflammation over time, identify mechanisms ileus. Methods  CSF-1−/−, TLR4 non-chimera chimera mice were single-shot intraperitoneal injected with ultrapure lipopolysaccharide (UP-LPS) studied up 4 days. Subgroups TLR4WT additionally intravenously exogenous recombinant (rmIL-6) or soluble receptor blocking antibody (anti-sIL-6R mAB). Key Results  Hemopoietic independently UP-LPS-induced 24 h, but chemotactic muscularis neutrophil extravasation not causatively involved lacking CSF-1-dependent macrophages died prematurely. Synergy determined severity mortality correlated synergistic cell lineage specific transcription inflammatory mediators like within intestinal muscularis. Circulating levels LPS dose dependent, rmIL-6 did spark off self-perpetuating response triggering ileus. Sustained therapeutic inhibition functional efficiently ameliorated late while preemptive antibody-mediated IL-6R blockade marginally effective mitigating However, prevent endotoxin-associated nor it alter circulating levels. Conclusions & Inferences  A time-delayed bone marrow-driven mechanism exists, synergize thereby prolonging fueling inflammation. Importantly, via IL-6R/gp130 drives ileus, yet regulate endotoxic shock.