Paeoniflorin diminishes ConA-induced IL-8 production in primary human hepatic sinusoidal endothelial cells in the involvement of ERK1/2 and Akt phosphorylation.
Liver diseases are closely associated with elevated levels of interleukin-8 (IL-8), suggesting the ability to inhibit IL-8 production could enhance the treatment of liver diseases. Paeoniflorin is a major active constituent of dried Paeoniae Radix Alba root (Baishao in Chinese) which is widely used in China to treat liver diseases. We examined the effects and underlying mechanisms of paeoniflorin on IL-8 production in primary human hepatic sinusoidal endothelial cells (HHSECs). Concanavalin A (ConA) at 20 μg/mL produced a 5.2-fold increase in IL-8 mRNA by 8h, and a 14.2-fold rise in IL-8 levels by 16 h. Inhibition of MEK (ERK kinase) and extracellular signal-regulated kinase (ERK) by PD98059 and U0126, or inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 blocked both ConA-induced IL-8 mRNA expression and IL-8 secretion. Paeoniflorin reduced ConA-induced IL-8 mRNA expression and IL-8 release by 57.9% and 52.8%, respectively, and also decreased ConA-stimulated phosphorylation of ERK1/2 and Akt, suggesting paeoniflorin inhibits IL-8 expression and release by inhibiting the ERK1/2 and Akt pathways. Combining paeoniflorin with U0126 or LY294002 at low doses showed supra-additive inhibition of not only phospho-ERK1/2 and phospho-Akt by 46.4% and 35.0%, but also IL-8 release by 42.4% and 36.1% and IL-8 mRNA expression by 43.5% and 31.8%, respectively. In conclusion, paeoniflorin most likely contributes to the therapy for liver disease by exerting anti-inflammatory effects on HHSECs through blocking IL-8 secretion via downregulation of ERK1/2 and Akt phosphorylation.
Institute of Inflammation and Immune Diseases, Department of Pathophysiology, Key Immunopharmacology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong, PR China.
Wen-Guang
WG
Gong
Center Laboratory, Shantou University Medical College, Guangdong, PR China.
Jue-Long
JL
Lin
Institute of Inflammation and Immune Diseases, Department of Pathophysiology, Key Immunopharmacology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong, PR China. Electronic address: nqx_1961@163.com.
Qing-Xia
QX
Niu
Institute of Inflammation and Immune Diseases, Department of Pathophysiology, Key Immunopharmacology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong, PR China.
Hong-Mei
HM
Wang
Institute of Inflammation and Immune Diseases, Department of Pathophysiology, Key Immunopharmacology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong, PR China.
Yan-Chun
YC
Zhou
Institute of Inflammation and Immune Diseases, Department of Pathophysiology, Key Immunopharmacology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong, PR China.
Shao-Ying
SY
Chen
Institute of Inflammation and Immune Diseases, Department of Pathophysiology, Key Immunopharmacology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong, PR China.
Guo-Wu
GW
Liang
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D039821:Monoterpenes / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D006027:Glycosides
D000893:Anti-Inflammatory Agents; D003208:Concanavalin A; D048049:Extracellular Signal-Regulated MAP Kinases; D005960:Glucosides; D016209:Interleukin-8; D039821:Monoterpenes; D051058:Oncogene Protein v-akt; C508606:CXCL8 protein, human; C015423:peoniflorin; D006027:Glycosides
Concanavalin A; Hepatic sinusoidal endothelial cells; Interleukin-8; Paeoniflorin