ROLE OF TOLL-LIKE RECEPTORS (TLR4) IN CAERULEIN INDUCED PANCREATITIS.

Abstract

TLR’s (toll-like receptors) play an important role in activating innate immune response to pathogen-related molecules hence also known as pattern recognition receptors (PRR’s). It is expressed on monocytes, neutrophils and macrophages. It binds to LPS and is identified as a type I transmembrane protein with extracellular domains containing leucine-rich repeats that may participate in ligand recognition. Acute pancreatitis is characterized by rapid production and release of inflammatory cytokines, which play a major role in the local pancreatic and systemic complications of the disease. The purpose of this study was to determine whether pathologic progression of acute pancreatitis is altered in the absence of TLR4 receptors. Method: Acute pancreatitis was induced by administering 12 hourly i.p. injections of caerulein (50 μg/kg) in Wild type and TLR4 knockout mice. Control mice received normal saline injections. Mice were sacrificed one hour after the last injection. The severity of pancreatitis was determined by measuring serum amylase activity, pancreatic water content, and sequestration of neutrophils (quantitated by myeloperoxidase activity) in the pancreatic tissue and by histological assessment of acinar cell injury. Results: Administration of caerulein for 12 hours resulted in pancreatic edema, hyperamylasemia, increased pancreatic MPO activity and pancreatic acinar cell necrosis in wild type mice. In contrast, caerulein administration to TLR4 knockout mice resulted in significantly less severe pancreatitis. Serum amylase was reduced more than 1.6 fold in TLR4 −/ − as compared to wild type mice. Pancreatic water content was reduced from 83.3±0.4 in wild type to 79.5±0.4 in TLR4 −/ − mice (p ≤ 0.05) after 12 caerulein i.p. injections. MPO activity in the pancreas after caerulein administration was significantly reduced from 363.3±58.5 in wild type to 88.0±9.7 in TLR4 −/ − mice (p ≤ 0.05). Similarly acinar cell necrosis was reduced to 6.8±0.9 as compared to 17.3±1.5 in wild type mice (p ≤ 0.05). Conclusions: These results demonstrate that the severity of acute pancreatitis is ameliorated in the mice in which TLR4 receptor has been genetically deleted. Furthermore, these results suggest that TLR4 play a significant pro-inflammatory role in the progression of acute pancreatitis.