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RECEPTORS AND SIGNAL TRANSDUCTION

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

Department of Pharmacology, National University of Singapore, Singapore

Submitted 13 August 2007 ; accepted in final form 17 December 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 NF-B. However, the signaling mechanisms by which the SP-NK1R interaction induces NF-B activation and chemokine production remain unclear. To that end, in the present study, we investigated the participation of PKC in SP-induced chemokine production in pancreatic acinar cells. In this study, we showed that SP stimulated an early phosphorylation of PKC isoform PKC- followed by increased activation of MAPKKK MEKK1 and MAPK ERK and JNK as well as transcription factor NF-B and activator protein-1 driven chemokine production. Depletion of PKC- with its inhibitor rottlerin or the specific PKC- translocation inhibitor peptide dose dependently decreased SP-induced PKC-, MEKK1, ERK, JNK, NF-B, and AP-1 activation. Moreover, rottlerin as well as PKC- translocation inhibitor inhibited SP-induced chemokine production in a concentration-dependent manner. We also demonstrated that PKC- activation was attenuated by CP96345, a selective NK1R antagonist, thus showing that PKC- activation was indeed mediated by SP in pancreatic acinar cells. These results show that PKC- is an important proinflammatory signal transducer for SP-NK1R-induced chemokine production in pancreatic acinar cells.

protein kinse C-; mitogen-activated protein kinase kinase kinase-1; extracellular signal-regulated kinase; c-Jun NH₂-terminal kinase; nuclear factor-B; activator protein-1