Role of PKC-delta on substance P-induced chemokine synthesis in pancreatic acinar cells.
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 alpha, and MIP-2 in pancreatic acinar cells via the activation of NF-kappaB. However, the signaling mechanisms by which the SP-NK1R interaction induces NF-kappaB 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-delta followed by increased activation of MAPKKK MEKK1 and MAPK ERK and JNK as well as transcription factor NF-kappaB and activator protein-1 driven chemokine production. Depletion of PKC-delta with its inhibitor rottlerin or the specific PKC-delta translocation inhibitor peptide dose dependently decreased SP-induced PKC-delta, MEKK1, ERK, JNK, NF-kappaB, and AP-1 activation. Moreover, rottlerin as well as PKC-delta translocation inhibitor inhibited SP-induced chemokine production in a concentration-dependent manner. We also demonstrated that PKC-delta activation was attenuated by CP96345, a selective NK1R antagonist, thus showing that PKC-delta activation was indeed mediated by SP in pancreatic acinar cells. These results show that PKC-delta is an important proinflammatory signal transducer for SP-NK1R-induced chemokine production in pancreatic acinar cells.
Ramnath
Raina Devi
RD
Dept. of Pharmacology, National Univ. of Singapore, Yong Loo Lin School of Medicine, Centre for life Sciences, 28 Medical Drive, Singapore 117456.
Sun
Jia
J
Adhikari
Sharmila
S
Zhi
Liang
L
Bhatia
Madhav
M
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054405:Chemokine CCL3 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D046790:Pancreas, Exocrine / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000098:Acetophenones; D001578:Benzopyrans; D001713:Biphenyl Compounds; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016328:NF-kappa B; D064729:Neurokinin-1 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D018040:Receptors, Neurokinin-1; D018808:Transcription Factor AP-1; D013373:Substance P; C085746:rottlerin; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C066892:CP 96345