Excretory-secretory products from Paragonimus westermani increase nitric oxide production in microglia in PKC-dependent and -independent manners.
Excretory-secretory products (ESP) from helminthic parasites may play pivotal roles in the immune regulation in hosts. Previously, we reported that ESP produced from Paragonimus westermani induced morphological activation of microglial cells and markedly stimulated nitric oxide (NO) production via activation of mitogen-activated protein kinases (MAPKs). In the present study, we investigated the role of protein kinase C and protein kinase A in MAPKs-dependent NO production by ESP. We found that treatment with protein kinase C inhibitor Go6976 strongly inhibited the phosphorylation of p38 and JNK, but not ERK, of MAPKs and decreased the production of NO in ESP-stimulated microglial cells. Inhibition of ERK, p38 or PKC decreased the ESP-induced activation of NF-kappaB, an important transcription factor for iNOS expression. Furthermore, ESP increased the level of p-CREB in microglial cells. However, adenylyl cyclase activator (forskolin), adenylyl cyclase inhibitor (SQ22536), cAMP analogue (db-cAMP) or protein kinase A inhibitor (H89) was not able to change iNOS expression and NO production in ESP-treated microglial cells. It implies that the cAMP-PKA-CREB pathway is not implicated in the ESP-evoked NO production in microglial cells. Thus, our results indicate that ESP stimulates microglial expression of iNOS via both PKC-dependent and -independent MAPKs phosphorylation and NF-kappaB activation.
Jin
Youngnam
Y
Department of Pharmacology and Physiology, University of Rochester, School of Medicine, Rochester, NY 14627, USA.
Choi
In Young
IY
Kim
Chunsook
C
Hong
Suyoung
S
Kim
Won-Ki
WK
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology; D002478:Cells, Cultured; D002494:Central Nervous System Infections / Q000378:metabolism / Q000469:parasitology / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism* / Q000469:parasitology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D017628:Microglia / Q000378:metabolism* / Q000469:parasitology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010237:Paragonimiasis / Q000378:metabolism* / Q000503:physiopathology; D048492:Paragonimus westermani / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009569:Nitric Oxide; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases