Activation of Phosphoinositide 3-Kinase, Protein Kinase C, and Extracellular Signal-Regulated Kinase Is Required for Oridonin-Enhanced Phagocytosis of Apoptotic Bodies in Human Macrophage-Like U937 Cells

Journal of Pharmacological Sciences

Song You²  Satoshi Onodera³  Takashi Ikejima¹  Yan-Qiu Liu¹  Shin-ichi Tashiro³ 

[1] China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University;Laboratory of Natural Product Biotechnology, Shenyang Pharmaceutical University;Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University

关键词: oridonin;    phagocytosis;    phosphoinositide 3-kinase;    protein kinase C;    extracellular signal-regulated kinase;   

DOI  :  10.1254/jphs.FPJ05005X

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(35)Cited-By(15)Our previous study showed that oridonin isolated from Rabdosia rubescens enhanced phagocytosis of apoptotic cells by macrophage-like U937 cells through tumor necrosis factor (TNF) α and interleukin (IL)-1β release. In this study, we further investigated signaling events involved in oridonin-augmented phagocytosis. Phagocytic stimulation was significantly suppressed by inhibitors, including a phosphoinositide 3-kinases (PI3K) inhibitor (wortmannin), a protein kinase C (PKC) inhibitor (stauroporine), and a phospholipase C (PLC) inhibitor (U73122). Exposure of U937 cells to oridonin caused an increase in PKC activity time- dependently, which was prevented by pretreatment with inhibitors of PI3K and PLC. Simultaneously, the activation of protein kinase B (PKB/Akt) and the increased expression of PLCγ2 were also blocked by wortmannin. In addition, an extracellular signal-regulated kinase (ERK) MAPK inhibitor, PD98059, suppressed oridonin-augmented phagocytosis, whereas the p38 MAPK inhibitor (SB203580) and c-Jun N-terminal kinase (JNK) MAPK inhibitor (SP98059) had no inhibitory effect. Furthermore, pretreatment of U937 cells with anti-TNFα and anti-IL-1β antibodies blocked oridonin-induced phagocytic stimulation as well as phosphorylation of ERK, but did not block the activation of PKC, indicating that these signaling events are triggered by oridonin, whereas secreted TNFα or IL-1β only activate the ERK-dependent pathway. Taken together, oridonin is suggested to enhance phagocytosis of apoptotic bodies by activating PI3K, PKC, and ERK-dependent pathways.

【 授权许可】

Unknown