Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators including chemokines and substance P (SP) are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine MCP-1 in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly SP levels in the pancreas and pancreatic acinar cell expression of NK-1R, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis.This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and determine if it leads to proinflammatory signalling such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of CC chemokine MCP-1 and MIP-1 as well as CXC chemokine MIP-2.Furthermore SP also increased NF-B activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-B pathway, since the increased in chemokine production was completely attenuated when pancreatic acini were pre-treated with the selective NF-B inhibitor, Nemo binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-B dependent.