Attenuation of acute pancreatitis by peroxisome proliferator-activated receptor-α in rats: the effect on Toll-like receptor signaling pathways.
OBJECTIVE
The peroxisome proliferator-activated receptor-α (PPAR-α) has attracted considerable attention for its anti-inflammatory properties; however, Toll-like receptor (TLR) pathways have an essential proinflammatory role in acute pancreatitis (AP). This study aimed to evaluate the attenuation of inflammation by PPAR-α and to investigate the interaction between PPAR-α and TLR pathways in AP.


METHODS
Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-α agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca(2+), pathological changes, myeloperoxidase activity, serum levels of interleukin (IL)-6, and intercellular adhesion molecule-1 (ICAM-1). The TLR2 and TLR4 messenger RNA (mRNA) and proteins were determined by real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. The mRNA expressions of target molecules of TLR pathways, including IL-6, IL-10, ICAM-1, and tumor necrosis factor α were also measured.


RESULTS
Treatment with WY14643 significantly decreased amylase, lipase, myeloperoxidase activity, pathological scores, IL-6, and ICAM-1 levels. The TLR2 and TLR4 mRNA and proteins were markedly decreased after treatment with WY14643, along with IL-6, ICAM-1, and tumor necrosis factor α mRNA levels. However, these effects were completely reversed by the coadministration of MK886.


CONCLUSIONS
Activation of PPAR-α played a protective role in AP, partially mediated by modulation of TLR pathways.
Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, People's Republic of China.
Jun-Li
JL
Ding
Zong-Guang
ZG
Zhou
Xiang-Yu
XY
Zhou
Bin
B
Zhou
Ling
L
Wang
Rong
R
Wang
Lan
L
Zhan
Xiao-Feng
XF
Sun
Yuan
Y
Li
D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002118:Calcium / Q000097:blood; D002108:Ceruletide; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007211:Indoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics; D008049:Lipase / Q000097:blood; D008297:Male; D020556:Neutrophil Infiltration / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010195:Pancreatitis / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000187:drug effects / Q000378:metabolism; D051193:Toll-Like Receptors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002722:Chlorobenzenes
D000681:Amylases; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D002118:Calcium; D002108:Ceruletide; D016207:Cytokines; D007211:Indoles; D018799:Intercellular Adhesion Molecule-1; D008049:Lipase; D047493:PPAR alpha; D009195:Peroxidase; D011743:Pyrimidines; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; C489640:Tlr9 protein, rat; C060893:MK-886; D002722:Chlorobenzenes; C006253:pirinixic acid