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Prothrombin Kringle-2 Activates Cultured Rat Brain Microglia¹

Jooyoung Ryu^2,*, Kyoung-jin Min^2,, Tai Youn Rhim, Tae Hyong Kim, Hankyoung Pyo^*, Byungkwan Jin^,, Seung-Up Kim, Ilo Jou^*, Soung Soo Kim and Eun-hye Joe^3,*,,

^* Department of Pharmacology, Neuroscience Graduate Program, and Brain Disease Research Center, Ajou University School of Medicine, Suwon, Korea; and Department of Biochemistry, College of Science, Yonsei University, Seoul, Korea

Microglia, the major immune effector cells in the CNS, become activated when the brain suffers injury. In this study, we observed that prothrombin, a zymogen of thrombin, induced NO release and mRNA expression of inducible NO synthase, IL-1, and TNF- in rat brain microglia. The effect of prothrombin was independent of the protease activity of thrombin since hirudin, a specific inhibitor of thrombin, did not inhibit prothrombin-induced NO release. Furthermore, factor Xa enhanced the effect of prothrombin on microglial NO release. Kringle-2, a domain of prothrombin distinct from thrombin, mimicked the effect of prothrombin in inducing NO release and mRNA expression of inducible NO synthase, IL-1, and TNF-. Prothrombin and kringle-2 both triggered the same intracellular signaling pathways. They both activated mitogen-activated protein kinases and NF-B in a similar pattern. NO release stimulated by either was similarly reduced by inhibitors of the extracellular signal-regulated kinase pathway (PD98059), p38 (SB203580), NF-B (N-acetylcysteine), protein kinase C (Go6976, bisindolylmaleimide, and Ro31-8220), and phospholipase C (D609 and U73122). These results suggest that prothrombin can activate microglia, and that, in addition to thrombin, kringle-2 is a domain of prothrombin independently capable of activating microglia.

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