| First Author | Buchholz BM | Year | 2012 |
| Journal | Neurogastroenterol Motil | Volume | 24 |
| Issue | 7 | Pages | 658-69, e294 |
| PubMed ID | 22489868 | Mgi Jnum | J:323161 |
| Mgi Id | MGI:6843184 | Doi | 10.1111/j.1365-2982.2012.01914.x |
| Citation | Buchholz BM, et al. (2012) Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock. Neurogastroenterol Motil 24(7):658-69, e294 |
| abstractText | 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 TLR4(WT) 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. |
