Potential role of the TLR4/IRAK-4 signaling pathway in the pathophysiology of acute pancreatitis in mice.
OBJECTIVE
Toll-like receptor 4 (TLR4) is potentially associated with acute pancreatitis (AP), but its exact role remains controversial. IL-1 receptor-associated kinase 4 (IRAK-4) is a common mediator of Toll-like receptors pathways, with an essential role in transducing downstream signals. This study investigates the potential role of the TLR4 pathway, in particular IRAK-4, in a murine model of AP.


METHODS
Acute pancreatitis was induced in wild-type and TLR4-deficient mice by intraperitoneal injections of caerulein (50 microg/kg). Pancreatic pathological scores and myeloperoxidase activity were dynamically measured, along with pancreatic TLR4 and IRAK-4 mRNA and protein.


RESULTS
In wild-type mice, pathological scores and myeloperoxidase activity were rapidly increased at 1, 2 and 4 h, followed by alleviation at 12 and 24 h. In TLR4-deficient mice, they were slightly increased within 2 h, but became more severe at 12 and 24 h. IRAK-4 mRNA and protein were significantly down-regulated at 1, 2 and 4 h in wild-type mice. Unexpectedly, TLR4-deficient mice showed more profound reductions of IRAK-4 mRNA and protein at the same time.


CONCLUSIONS
TLR4 deficiency delayed the initiation of pancreatitis, implying a potential role for TLR4 during AP. IRAK-4 might function during AP, but independently of TLR4.
State Key Laboratory of Biotherapy, Institute of Digestive Surgery, West China Hospital, Sichuan University, Sichuan, People's Republic of China. dingjunliletters@163.com
Jun-Li
JL
Ding
Yuan
Y
Li
Xiang-Yu
XY
Zhou
Ling
L
Wang
Bin
B
Zhou
Rong
R
Wang
Hong-Xiang
HX
Liu
Zong-Guang
ZG
Zhou
D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009195:Peroxidase / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002108:Ceruletide; D009195:Peroxidase; D053592:Interleukin-1 Receptor-Associated Kinases