HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901620v1 183/10/6744    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Buchholz, B. M. Articles by Bauer, A. J. M. PubMed PubMed Citation Articles by Buchholz, B. M. Articles by Bauer, A. J. M.

Nonhemopoietic Cell TLR4 Signaling Is Critical in Causing Early Lipopolysaccharide-Induced Ileus¹

Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA 15261

Endotoxin-mediated ileus is poorly understood. Our objective was to mechanistically investigate the role of cell-specific TLR4 expression/signaling in causing gastrointestinal dysmotility. TLR4 chimeras and CSF-1-dependent macrophage-deficient mice were subjected to i.p. ultrapure (UP)-LPS (5 mg/kg). At 6 h, gastric emptying and gastrointestinal transit assessed in vivo motility, and jejunal circular muscle contractility was measured in vitro. Muscularis infiltration of neutrophils and monocytes were counted, and intestinal muscularis inflammatory mediators were quantified by quantitative PCR. Demonstrating TLR4 dependency, UP-LPS-induced gastric stasis and ileus of TLR4^WT mice were absent in mutant TLR4^LPS-d mice. Unexpectedly, engraftment of TLR4-mutant bone marrow into TLR4-competent mice (bmTLR4^LPS-d/TLR4^WT) exhibited a significant transit delay to UP-LPS similar to bmTLR4^WT/TLR4^WT mice. CSF-1^–/– mice were not protected from ileus. Contrary, UP-LPS-treated bmTLR4^WT/TLR4^LPS-d and bmTLR4^LPS-d/TLR4^LPS-d mice had normal transit. No leukocytic infiltration was detected at 6 h. Spontaneous jejunal contractions were markedly suppressed in UP-LPS-treated TLR4-competent mice, but bethanechol-stimulated contractions were not altered by UP-LPS in any group. UP-LPS-induced inflammatory mRNAs in a TLR4-dependent manner, but TLR4 mRNA itself was not significantly altered. In chimera mice, UP-LPS induction of IL-1β and IL-10 were hemopoietic dependent, and GM-CSF was nonhemopoietic dependent, whereas IL-6 and inducible NO synthase were derived from both cell types. Hemopoietic and nonhemopoietic cells contribute to TLR4-sensitive muscularis inflammatory signaling, but nonhemopoietic TLR4 signaling plays an exclusive primary role in causing functional UP-LPS-induced gastric stasis and ileus. Direct LPS suppression of spontaneous contractility participates in mediating early TLR4-transduced dysmotility.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grants R01-GM58241, R01-DK068610, P50-GM-53789, and DK02488.

² Address correspondence and reprint requests to Dr. Anthony J. M. Bauer, Associate Professor of Medicine, Department of Medicine/Gastroenterology, University of Pittsburgh, S-849 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail address: tbauer{at}pitt.edu

³ Abbreviations used in this paper: ENS, enteric nervous system; GC, geometric center; ICC, interstitial cells of cajal; iNOS, inducible nitric oxide synthase; UP-LPS, ultrapure LPS.