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

Abstract

Background Early murine endotoxin-induced ileus at 6 hours 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 injected with intraperitoneal 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 hours, 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 selfperpetuating 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 and 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, I L-6 signaling via IL-6R/gp130 drives late ileus, yet it did not regulate mortality in endotoxic shock.

Cytokines in abdominal exudate and serum predict small bowel obstruction following appendectomy

“…The local inflammatory status may have a significant modulating role in bowel function. A previous study showed that IL‐6 signalling via IL‐6R/gp130 drives late ileus, and sustained therapeutic inhibition of functional IL‐6 signalling efficiently ameliorated late ileus 33 . In our study, the levels of IL‐1β, IL‐6 and TNF‐α in abdominal exudate in the SBO group were significantly higher than that in the non‐SBO group.…”

“…A previous study showed that IL-6 signalling via IL-6R/gp130 drives late ileus, and sustained therapeutic inhibition of functional IL-6 signalling efficiently ameliorated late ileus. 33 In our study, the ). The AUC for peritoneal IL-6, preoperative serum CRP and perforated appendicitis was 0.904, 0.824 and 0.798, respectively, which indicated that both variables given above are reliable biomarkers for small bowel obstruction.…”

Preoperative Serum Interleukin-6 Is a Potential Prognostic Factor for Colorectal Cancer, including Stage II Patients

“…Clinically, significant correlations between elevated serum IL-6 levels and other clinical factors such as serum CEA [ 14 , 15 ], CRP [ 16 , 17 ], and bowel obstruction [ 18 , 19 ] have been previously reported. Further, it has also been reported that injections of CEA into murine models induced the release of cytokines, including IL-6, in vivo [ 20 ].…”

“…Endotoxins are found in the outer membrane of Gram-negative bacteria and are released by the destruction of the bacterial cell walls. They are known to cause various biological responses, including sepsis [ 18 ]. Furthermore, endotoxins activate inflammatory mediators such as IL-6 within the intestinal muscularis [ 19 ].…”

Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus

“…In contrast, activation of TLR4 signaling solely in hemopoietic-derived cells results in a time-delayed onset of gastrointestinal dysmotility after 24 h of endotoxemia. This late endotoxin-induced ileus in mice is known to be driven by inflammatory cytokines, and, in particular, interleukin (IL)-6 plays a central role (5). Hemopoietic and nonhemopoietic cells are major sources of IL-6, as well as numerous other inflammatory mediators.…”