Valatas Vassilis, Kolios George, Manousou Pinelopi, Notas George, Xidakis Costas, Diamantis Ioannis, Kouroumalis Elias
Gastroenterology Department, Faculty of Medicine, University of Crete, Heraklion GR-71003, Greece.
Br J Pharmacol. 2004 Feb;141(3):477-87. doi: 10.1038/sj.bjp.0705633. Epub 2004 Jan 12.
Kupffer cells (KC) and lipopolysaccharide (LPS) interaction is the initial event leading to hepatic inflammation and fibrosis in many types of liver injury. We studied chemokine secretion by KC activated with LPS and the possible effect of the somatostatin analogue octreotide, in the regulation of this process. KC isolated from Sprague-Dawley rats were cultured in the presence of LPS added alone or with different concentrations of octreotide for 24 and 48 h, and chemokine production was assessed in culture supernatants by ELISA. CC chemokine mRNA expression was assessed by semiquantitative RT-PCR. Vehicle-stimulated KC produced a basal amount of CC and CXC chemokines. LPS-stimulated KC secreted significantly increased amounts of IL-8 (GRO/CINC-1) (P<0.001), MIP-2 (P<0.001), MCP-1 (P<0.001), and RANTES (P<0.01). Octreotide inhibited LPS-induced secretion of the CC chemokines MCP-1 (P<0.05) and RANTES (P<0.05), but not the CXC chemokines IL-8 (GRO/CINC-1) and MIP-2, in a concentration-dependent manner. Downregulation of basal and LPS-induced mRNA expression of the CC chemokines was also observed in the presence of octreotide. Pretreatment with phosphatidylinositol 3 (PI3)-kinase inhibitors reduced chemokine production by LPS-treated KC in both the mRNA and protein level. Furthermore, it prevented the octreotide inhibitory effect on LPS-induced chemokine secretion, indicating a possible involvement of the PI3-kinase pathway. In conclusion, these data demonstrate that chemokine secretion by KC can be differentially regulated by octreotide, and suggest that this somatostatin analogue may have immunoregulatory effects on resident liver macrophages. British Journal of Pharmacology (2004) 141, 477-487. doi:10.1038/sj.bjp.0705633
库普弗细胞（KC）与脂多糖（LPS）的相互作用是导致多种类型肝损伤中肝脏炎症和纤维化的起始事件。我们研究了LPS激活的KC分泌趋化因子的情况，以及生长抑素类似物奥曲肽在调节这一过程中的可能作用。从Sprague-Dawley大鼠分离出的KC在单独添加LPS或添加不同浓度奥曲肽的情况下培养24小时和48小时，通过ELISA法评估培养上清液中的趋化因子产生情况。通过半定量RT-PCR评估CC趋化因子mRNA表达。载体刺激的KC产生基础量的CC和CXC趋化因子。LPS刺激的KC分泌的IL-8（GRO/CINC-1）（P<0.001）、MIP-2（P<0.001）、MCP-1（P<0.001）和RANTES（P<0.01）显著增加。奥曲肽以浓度依赖的方式抑制LPS诱导的CC趋化因子MCP-1（P<0.05）和RANTES（P<0.05）的分泌，但不抑制CXC趋化因子IL-8（GRO/CINC-1）和MIP-2。在奥曲肽存在的情况下，也观察到CC趋化因子基础和LPS诱导的mRNA表达下调。用磷脂酰肌醇3（PI3）-激酶抑制剂预处理可在mRNA和蛋白质水平上降低LPS处理的KC产生趋化因子的量。此外，它阻止了奥曲肽对LPS诱导的趋化因子分泌的抑制作用，表明PI3-激酶途径可能参与其中。总之，这些数据表明KC分泌趋化因子可被奥曲肽差异性调节，并提示这种生长抑素类似物可能对肝脏驻留巨噬细胞具有免疫调节作用。《英国药理学杂志》（2004年）141卷，477 - 487页。doi:10.1038/sj.bjp.0705633
