PMID- 20508155
OWN - NLM
STAT- MEDLINE
DCOM- 20100830
LR  - 20211020
IS  - 1522-1547 (Electronic)
IS  - 0193-1857 (Print)
IS  - 0193-1857 (Linking)
VI  - 299
IP  - 2
DP  - 2010 Aug
TI  - Dominant role of the MyD88-dependent signaling pathway in mediating early 
      endotoxin-induced murine ileus.
PG  - G531-8
LID - 10.1152/ajpgi.00060.2010 [doi]
AB  - 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-beta (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-1beta, 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.
FAU - Buchholz, Bettina M
AU  - Buchholz BM
AD  - Dept. of Medicine/Gastroenterology; Univ. of Pittsburgh, Pennsylvania 15261, USA.
FAU - Billiar, Timothy R
AU  - Billiar TR
FAU - Bauer, Anthony J
AU  - Bauer AJ
LA  - eng
GR  - DK02488/DK/NIDDK NIH HHS/United States
GR  - P50-GM-53789/GM/NIGMS NIH HHS/United States
GR  - R01-DK-068610/DK/NIDDK NIH HHS/United States
GR  - R01-GM-58241/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100527
PL  - United States
TA  - Am J Physiol Gastrointest Liver Physiol
JT  - American journal of physiology. Gastrointestinal and liver physiology
JID - 100901227
RN  - 0 (Adaptor Proteins, Vesicular Transport)
RN  - 0 (Endotoxins)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (TICAM-1 protein, mouse)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Adaptor Proteins, Vesicular Transport/*metabolism
MH  - Animals
MH  - Endotoxins/*metabolism
MH  - Ileus/*etiology
MH  - Inflammation Mediators/metabolism
MH  - Intestinal Mucosa/metabolism
MH  - Intestines/drug effects
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Mutant Strains
MH  - Muscle, Smooth/drug effects/metabolism
MH  - Myeloid Differentiation Factor 88/genetics/*metabolism
MH  - *Signal Transduction
MH  - Toll-Like Receptor 4/*metabolism
MH  - Transcriptional Activation
PMC - PMC2928536
EDAT- 2010/05/29 06:00
MHDA- 2010/08/31 06:00
PMCR- 2011/08/01
CRDT- 2010/05/29 06:00
PHST- 2010/05/29 06:00 [entrez]
PHST- 2010/05/29 06:00 [pubmed]
PHST- 2010/08/31 06:00 [medline]
PHST- 2011/08/01 00:00 [pmc-release]
AID - ajpgi.00060.2010 [pii]
AID - GI-00060-2010 [pii]
AID - 10.1152/ajpgi.00060.2010 [doi]
PST - ppublish
SO  - Am J Physiol Gastrointest Liver Physiol. 2010 Aug;299(2):G531-8. doi: 
      10.1152/ajpgi.00060.2010. Epub 2010 May 27.