Proteasome inhibitor-induced cyclooxygenase-2 expression in Raw264.7 cells is potentiated by inhibition of c-Jun N-terminal kinase activation.
Prostaglandins play regulatory roles in a variety of physiological and pathological processes in immune response and inflammation. MG132, proteasome inhibitor, is known to anti-tumor agent activity and anti-inflammation with inhibitory property of NF-kappaB. We investigated the effect of MG132 on the expression of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of PGE(2), using macrophage cell line, Raw264.7. Our results showed that COX-2 expression is up-regulated by MG132 treatment and that this induction of COX-2 is regulated in part at the transcriptional level. In addition, we demonstrated the signal transduction pathway of mitogen-activated protein kinase (MAP kinase) in MG132-induced COX-2 expression. The p38 MAPK inhibitor (SB 203580) prevented MG132-induced COX-2 expression, whereas c-Jun N-terminal kinase (JNK) inhibitor (SP 600125) and MAPK kinase 4 (MKK4)-DN (dominant negative mutant) and MKK7-DN significantly enhanced COX-2 expression. These results suggest that MG132-induced COX-2 expression is associated with the activation of p38 MAPK and the inhibition of JNK signaling pathways.
Woo
Kyung Jin
KJ
Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, Republic of Korea.
Park
Jong-Wook
JW
Kwon
Taeg Kyu
TK
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage*; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007976:Leupeptins / Q000008:administration & dosage*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D061988:Proteasome Inhibitors
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde