Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Neurogastroenterol Motil. 2012 Jul;24(7):658-69, e294. doi: 10.1111/j.1365-2982.2012.01914.x. Epub 2012 Apr 10.
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.
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).
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.
尽管造血细胞的分子激活包括显著的 IL-6 mRNA 诱导，但在 6 小时的早期鼠内毒素诱导性肠梗阻中，仅由非造血 TLR4/MyD88 信号转导介导。我们的目标是定义造血细胞在 LPS/TLR4 触发的肠梗阻和炎症中的作用随时间的推移，并确定肠梗阻的机制。
CSF-1(-/-)、TLR4 非嵌合体和 TLR4 嵌合体小鼠单次腹腔注射超纯脂多糖 (UP-LPS)，并研究至 4 天。TLR4(WT)小鼠的亚组还静脉注射外源性重组 IL-6 (rmIL-6)或鼠可溶性 IL-6 受体阻断抗体 (抗-sIL-6R mAB)。
造血 TLR4 信号转导独立介导 UP-LPS 诱导的 24 小时肠梗阻，但趋化性肌层中性粒细胞渗出并非因果关系，缺乏 CSF-1 依赖性巨噬细胞的小鼠过早死亡。造血细胞和非造血细胞的协同作用决定了肠梗阻的严重程度和死亡率，这与肠道肌层中炎症介质（如 IL-6）的协同细胞谱系特异性转录相关。循环 IL-6 水平与 LPS 剂量呈依赖性，但外源性 rmIL-6 不会引发自我延续的炎症反应，从而引发肠梗阻。持续的功能性 IL-6 信号转导抑制治疗可有效改善晚期肠梗阻，而预防性抗体介导的 IL-6R 阻断在缓解肠梗阻方面仅略有效果。然而，IL-6R 阻断既不能防止内毒素相关的死亡率，也不能改变循环 IL-6 水平。
存在一种延迟的骨髓驱动的鼠内毒素诱导性肠梗阻机制，造血细胞与非造血细胞协同作用，从而延长肠梗阻并加剧肠道炎症。重要的是，通过 IL-6R/gp130 传递的 IL-6 信号驱动晚期肠梗阻，但它并未调节内毒素休克中的死亡率。
