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J. Biol. Chem., Vol. 278, Issue 19, 17368-17378, May 9, 2003

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Thrombin Induces Nitric-oxide Synthase via G_12/13-coupled Protein Kinase C-dependent I-B Phosphorylation and JNK-mediated I-B Degradation^*

Keon Wook Kang, So Yeon Choi, Min Kyung Cho, Chang Ho Lee, and Sang Geon Kim^§

From the National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, and  Department of Pharmacology and Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul 133-791, Korea

An imbalance between thrombin and antithrombin III contributed to vascular hyporeactivity in sepsis, which can be attributed to excess NO production by inducible nitric-oxide synthase (iNOS). In view of the importance of the thrombin-activated coagulation pathway and excess NO as the culminating factors in vascular hyporeactivity, this study investigated the effects of thrombin on the induction of iNOS and NO production in macrophages. Thrombin induced iNOS protein in the Raw264.7 cells, which was inhibited by a thrombin inhibitor, LB30057. Thrombin increased NF-B DNA binding, whose band was supershifted with anti-p65 and anti-p50 antibodies. Thrombin elicited the phosphorylation and degradation of I-B prior to the nuclear translocation of p65. The NF-B-mediated iNOS induction was stimulated by the overexpression of activated mutants of G_12/13 (G_12/13QL). Protein kinase C depletion inhibited I-B degradation, NF-B activation, and iNOS induction by thrombin or the iNOS induction by G_12/13QL. JNK, p38 kinase, and ERK were all activated by thrombin. JNK inhibition by the stable transfection with a dominant negative mutant of JNK1 (JNK1()) completely suppressed the NF-B-mediated iNOS induction by thrombin. Conversely, the inhibition of p38 kinase enhanced the expression of iNOS. In addition, JNK and p38 kinase oppositely controlled the NF-B-mediated iNOS induction by G_12/13QL. Hence, iNOS induction by thrombin was regulated by the opposed functions of JNK and p38 kinase downstream of G_12/13. In the JNK1() cells, thrombin did not increase either the NF-B binding activity or I-B degradation despite I-B phosphorylation. These results demonstrated that thrombin induces iNOS in macrophages via G₁₂ and G₁₃, which leads to NF-B activation involving the protein kinase C-dependent phosphorylation of I-B and the JNK-dependent degradation of phosphorylated I-B.

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