Attenuation of Acute Pancreatitis by Peroxisome Proliferator-Activated Receptor-α in Rats The Effect on Toll-Like Receptor Signaling Pathways

Objectives: The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) 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-alpha and to investigate the interaction between PPAR-alpha and TLR pathways in AP. Methods: Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-alpha agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca2+, 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 alpha 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 alpha mRNA levels. However, these effects were completely reversed by the coadministration of MK886. Conclusions: Activation of PPAR-alpha played a protective role in AP, partially mediated by modulation of TLR pathways.