Impairment of phosphatidylinositol signaling in acetylshikonin-treated neutrophils.
In rat neutrophils, formylmethionyl-leucyl-phenylalanine (fMLP)-induced inositol phosphate formation was concentration-dependently inhibited by acetylshikonin as well as by a putative phospholipase C (PLC) inhibitor [6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-p yrrole-2,5-dione (U73122). The IC50 value of acetylshikonin for the inhibition of inositol trisphosphate (IP3) formation was estimated to be 16.1 +/- 1.5 microM. The reduction of inositol phosphate levels appeared to reflect inhibition of PLC activity because the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) catalyzed by a soluble fraction from neutrophils was also inhibited by acetylshikonin (IC50 value 21.4 +/- 6.1 microM) over the same range of concentrations. Although acetylshikonin alone evoked Ca2+ and Mn2+ influx into neutrophils in Ca2+-containing medium, acetylshikonin, like U73122, inhibited Ca2+ release (IC50 value approximately 5.3 +/- 0.4 microM) from internal stores in Ca2+-free medium. These results indicate that acetylshikonin inhibits phosphatidylinositol signaling in neutrophils.
Wang
J P
JP
Department of Medical Research, Taichung Veterans General Hospital, Taiwan, Republic of China.
Kuo
S C
SC
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D000880:Anthraquinones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004365:Drugs, Chinese Herbal; D004963:Estrenes; D010716:Phosphatidylinositols; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D010738:Type C Phospholipases; C073944:acetylshikonin; D002118:Calcium