Dominant role of the MyD88-dependent signaling pathway in mediating early endotoxin-induced murine ileus
- 1 August 2010
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 299 (2), G531-G538
- https://doi.org/10.1152/ajpgi.00060.2010
Abstract
TLR4 ligation by pathogen-associated molecular patterns, such as Gram-negative bacteria-derived LPS, triggers a nonhematopoietic cell-mediated ileus during early endotoxemia. Our objective was to investigate the quantitative contributions of the two downstream signaling pathways of TLR4, namely the adapter proteins myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-1-resistance (TIR) domain-containing adaptor-inducing IFN-β (TRIF). Six hours after intraperitoneal injection of highly purified LPS (UP-LPS, 5 mg/kg), in vivo gastrointestinal transit and intestinal muscularis gene transcripts of inflammatory mediators chemokine (C-X-C motif) ligand 10, synonymous IP-10 (CXCL10), granulomonocyte colony stimulating factor (GM-CSF, synonymous CSF-2), IL-1β, IL-6, IL-10, and inducible NO synthase (iNOS) were assessed in mice with transgenic loss-of-function for MyD88 or TRIF. LPS-induced MyD88 and TRIF mRNA upregulation was quantified within the intestinal muscularis of TLR4-competent and TLR4-mutant mice, and MyD88 mRNA levels were additionally measured in TLR4 bone marrow chimeras. MyD88 deficiency completely protected mice from early endotoxin-induced ileus, while TRIF deficiency partially ameliorated ileus severity. LPS induction of the primary downstream signaling element MyD88 was TLR4 dependent and was derived in equal amounts from both the hematopoietic and the nonhematopoietic cells. Conversely, no induction of TRIF mRNA was detectable. Significant gene induction of all inflammatory mediators was dependent on intracellular signal transduction by MyD88, while the TRIF MyD88-independent pathway predominantly regulated the molecular levels of CXCL10. In summary, MyD88 and TRIF are nonredundant signaling pathways in early endotoxin-induced rodent ileus, but MyD88 is the essential adaptor molecule for transduction of early TLR4-induced ileus and inflammatory signaling. The dependency of ileus on individual adaptor protein pathways is also reflected in the manifestation of specific molecular inflammatory events within the intestinal muscularis externa.Keywords
This publication has 37 references indexed in Scilit:
- Toll-like Receptors 3, 4, and 7 Are Expressed in the Enteric Nervous System and Dorsal Root GangliaJournal of Histochemistry & Cytochemistry, 2009
- TLR4/MyD88/PI3K interactions regulate TLR4 signalingJournal of Leukocyte Biology, 2009
- Modulation of TLR Signaling by Multiple MyD88-Interacting Partners Including Leucine-Rich Repeat Fli-I-Interacting ProteinsPublished by The American Association of Immunologists ,2009
- Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signalsNature Immunology, 2009
- Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4Proceedings of the National Academy of Sciences, 2009
- Extracellular heat shock protein 90 induces interleukin-8 in vascular smooth muscle cellsBiochemical and Biophysical Research Communications, 2009
- Proinflammatory Role of Leukocyte-Derived Egr-1 in the Development of Murine Postoperative IleusGastroenterology, 2008
- Necrotic neurons enhance microglial neurotoxicity through induction of glutaminase by a MyD88-dependent pathwayJournal of Neuroinflammation, 2008
- Postnatal acquisition of endotoxin tolerance in intestinal epithelial cellsThe Journal of Experimental Medicine, 2006
- Pathogen Recognition and Innate ImmunityCell, 2006