Unknown

Dataset Information

0

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


ABSTRACT: 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.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.

SUBMITTER: Buchholz BM 

PROVIDER: S-EPMC3378783 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Buchholz B M BM   Chanthaphavong R S RS   Billiar T R TR   Bauer A J AJ  

Neurogastroenterology and motility 20120410 7


<h4>Background</h4>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.<h4>Methods</h4>CSF-1(-/-) , TLR4 non-chimera and TLR4 chimera mice were single-shot intraperitoneal injected with ultrapure l  ...[more]

Similar Datasets

| S-EPMC4858745 | biostudies-literature
| S-EPMC3931427 | biostudies-literature
| S-EPMC5715788 | biostudies-literature
| S-EPMC4018573 | biostudies-literature
| S-EPMC6294129 | biostudies-literature
| S-EPMC6307094 | biostudies-literature
| S-EPMC6379471 | biostudies-literature
| S-EPMC6137717 | biostudies-literature
| S-EPMC3936230 | biostudies-literature
| S-EPMC5063984 | biostudies-literature