Role of PKC- on substance P-induced chemokine synthesis in pancreatic acinar cells

Ramnath RD, Sun J, Adhikari S, Zhi L, Bhatia M. Role of PKCon substance P-induced chemokine synthesis in pancreatic acinar cells. Am J Physiol Cell Physiol 294: C683–C692, 2008. First published December 26, 2007; doi:10.1152/ajpcell.00360.2007.—Interaction of the neuropeptide substance P (SP) with its high-affinity neurokinin-1 receptor (NK1R) plays an important role in the pathophysiology of acute pancreatitis. SP is known to stimulate the production of chemokines monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1 , and MIP-2 in pancreatic acinar cells via the activation of NFB. However, the signaling mechanisms by which the SP-NK1R interaction induces NFB activation and chemokine production remain unclear. To that end, in the present study, we investigated the participation of PKC in SPinduced chemokine production in pancreatic acinar cells. In this study, we showed that SP stimulated an early phosphorylation of PKC isoform PKCfollowed by increased activation of MAPKKK MEKK1 and MAPK ERK and JNK as well as transcription factor NFB and activator protein-1 driven chemokine production. Depletion of PKCwith its inhibitor rottlerin or the specific PKCtranslocation inhibitor peptide dose dependently decreased SP-induced PKC, MEKK1, ERK, JNK, NFB, and AP-1 activation. Moreover, rottlerin as well as PKCtranslocation inhibitor inhibited SP-induced chemokine production in a concentration-dependent manner. We also demonstrated that PKCactivation was attenuated by CP96345, a selective NK1R antagonist, thus showing that PKCactivation was indeed mediated by SP in pancreatic acinar cells. These results show that PKCis an important proinflammatory signal transducer for SP-NK1R-induced chemokine production in pancreatic acinar cells.