PMID- 22188870
OWN - NLM
STAT- MEDLINE
DCOM- 20120509
LR  - 20211021
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 9
DP  - 2011 Dec 21
TI  - TLR4 dependent heparan sulphate-induced pancreatic inflammatory response is 
      IRF3-mediated.
PG  - 219
LID - 10.1186/1479-5876-9-219 [doi]
AB  - BACKGROUND: Degraded extracellular matrix can stimulate the innate immune system 
      via the Toll-Like Receptor-4 (TLR4). In the pancreas, syndecan-anchored heparan 
      sulphate (HS) on the ductal epithelium can be cleaved off its protein cores by 
      the proteases (trypsin and elastase) and potentially activate TLR4 signalling. 
      METHODS: To investigate this signalling event, a low sulphated HS (500 mug/ml) was 
      infused into the biliary-pancreatic duct of C57BL/6J wild-type mice. Phosphate 
      buffered saline (PBS) and lipopolysaccharide (LPS) were used as negative and 
      positive controls, respectively. Mice were sacrificed after 1, 3, 6, 9, and 48 
      hours and tissues were analysed for neutrophil and cytokine contents. In order to 
      study the TLR4 signalling pathway of HS in the pancreas, genetically engineered 
      mice lacking TLR4, Myeloid Differentiation primary response gene (88) (MyD88) or 
      Interferon Regulatory Factor 3 (IRF3) were subjected to pancreatic infusion of 
      HS. RESULTS: Neutrophil sequestration and corresponding myeloperoxidase (MPO) 
      activity in the pancreas were increased 9 hours following HS challenge. In 
      wild-type mice, the monocyte chemoattractant protein-1(MCP-1) increased at 3 
      hours after infusion, while RANTES increased after 9 hours.TLR4, MyD88, and IRF3 
      knockout mice showed an abrogated neutrophil recruitment and myeloperoxidase 
      activity in the HS group, while the LPS response was only abolished in TLR4 and 
      MyD88 knockouts. CONCLUSIONS: The results of this study show that HS is capable 
      of initiating a TLR4-dependent innate immune response in the pancreas which is 
      distinctly different from that induced by LPS. This inflammatory response was 
      mediated predominantly through IRF3- dependent pathway. Release of HS into the 
      pancreatic duct may be one important mediator in the pancreatic ductal defence.
FAU - Akbarshahi, Hamid
AU  - Akbarshahi H
AD  - Department of Clinical Sciences Lund, Lund University, BMC, D12, SE-221 84 Lund, 
      Sweden.
FAU - Axelsson, Jakob B F
AU  - Axelsson JB
FAU - Said, Katarzyna
AU  - Said K
FAU - Malmstrom, Anders
AU  - Malmstrom A
FAU - Fischer, Hans
AU  - Fischer H
FAU - Andersson, Roland
AU  - Andersson R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111221
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (Chemokine CCL5)
RN  - 0 (Chemotactic Factors)
RN  - 0 (Cytokines)
RN  - 0 (Disaccharides)
RN  - 0 (Interferon Regulatory Factor-3)
RN  - 0 (Irf3 protein, mouse)
RN  - 0 (Sugar Phosphates)
RN  - 0 (Toll-Like Receptor 4)
RN  - 551541VI0Y (eritoran)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 1.11.1.7 (Peroxidase)
SB  - IM
MH  - Animals
MH  - Chemokine CCL5/metabolism
MH  - Chemotactic Factors/pharmacology
MH  - Cytokines/metabolism
MH  - Disaccharides/pharmacology
MH  - Heparitin Sulfate/administration & dosage/*pharmacology
MH  - Inflammation/metabolism/*pathology
MH  - Interferon Regulatory Factor-3/deficiency/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Neutrophil Infiltration/drug effects
MH  - Pancreas/*metabolism/*pathology
MH  - Peroxidase/metabolism
MH  - Sugar Phosphates/pharmacology
MH  - Time Factors
MH  - Toll-Like Receptor 4/*metabolism
PMC - PMC3286488
EDAT- 2011/12/23 06:00
MHDA- 2012/05/10 06:00
PMCR- 2011/12/21
CRDT- 2011/12/23 06:00
PHST- 2011/05/03 00:00 [received]
PHST- 2011/12/21 00:00 [accepted]
PHST- 2011/12/23 06:00 [entrez]
PHST- 2011/12/23 06:00 [pubmed]
PHST- 2012/05/10 06:00 [medline]
PHST- 2011/12/21 00:00 [pmc-release]
AID - 1479-5876-9-219 [pii]
AID - 10.1186/1479-5876-9-219 [doi]
PST - epublish
SO  - J Transl Med. 2011 Dec 21;9:219. doi: 10.1186/1479-5876-9-219.