Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock1

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