Bazel S, Andrejko K M, Chen J, Deutschman C S
Department of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Shock. 1999 May;11(5):347-55.
Inflammatory stimulation of hepatic acute phase protein expression is, in part, modulated by tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-beta), and IL-6. These cytokines also may mediate some aspects of the persistent inflammation and metabolic dysregulation of sepsis. Cecal ligation and puncture (CLP) sepsis in male Sprague-Dawley rats inappropriately decreases hepatocellular transcription of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), carnitine palmitoyltransferase II (CPTII), acetyl CoA acyltransferase (ACA), and ornithine transcarbamylase (OTC). We hypothesize that 1) transcriptional reprogramming does not occur after simple inflammation induced by subcutaneous turpentine injection, 2) the pattern of acute phase gene expression after CLP differs from that following turpentine injection, and 3) the different responses reflect differences in the intrahepatic activity of TNFalpha/IL-1beta or IL-6. Gene expression, transcription factor activity, and cytokine abundance were determined after either a subcutaneous injection of turpentine or CLP. After turpentine injection, PEPCK, G6Pase, CPTII, ACA, and OTC expression were unchanged, different from previously reported data following CLP. Both turpentine injection and CLP increased expression of TNFalpha/IL-1beta-regulated alpha1-acid glycoprotein, and IL-6-regulated alpha2-macroglobulin and decreased expression of transthyretin (a negative acute phase protein). However, the magnitude and temporal pattern of expression differed. Turpentine injection increased the activity of the TNFalpha/IL-1beta-linked transcription factor NF-kappaB and the intrahepatic abundance of TNFalpha in a manner similar to that observed after CLP but only slightly altered the activity of the IL-6-linked transcription factor Stat-3 and intrahepatic IL-6 abundance. This differed significantly from observations after CLP. We conclude that CLP-induced alterations in hepatic gene expression may reflect differences in IL-6 activity.
肝脏急性期蛋白表达的炎症刺激部分受肿瘤坏死因子-α（TNFα）、白细胞介素-1β（IL-β）和IL-6调控。这些细胞因子也可能介导脓毒症持续炎症和代谢失调的某些方面。雄性Sprague-Dawley大鼠的盲肠结扎穿刺（CLP）脓毒症会不恰当地降低磷酸烯醇丙酮酸羧激酶（PEPCK）、葡萄糖-6-磷酸酶（G6Pase）、肉碱棕榈酰转移酶II（CPTII）、乙酰辅酶A酰基转移酶（ACA）和鸟氨酸转氨甲酰酶（OTC）的肝细胞转录。我们假设：1）皮下注射松节油诱导的单纯炎症后不会发生转录重编程；2）CLP后急性期基因表达模式与松节油注射后不同；3）不同反应反映了TNFα/IL-1β或IL-6肝内活性的差异。在皮下注射松节油或CLP后测定基因表达、转录因子活性和细胞因子丰度。注射松节油后，PEPCK、G6Pase、CPTII、ACA和OTC表达未改变，这与先前报道的CLP后数据不同。松节油注射和CLP均增加了TNFα/IL-1β调控的α1-酸性糖蛋白以及IL-6调控的α2-巨球蛋白的表达，并降低了甲状腺素运载蛋白（一种负急性期蛋白）的表达。然而，表达的幅度和时间模式不同。松节油注射以与CLP后观察到的方式类似的方式增加了TNFα/IL-1β相关转录因子NF-κB的活性以及肝内TNFα的丰度，但仅轻微改变了IL-6相关转录因子Stat-3的活性和肝内IL-6的丰度。这与CLP后的观察结果有显著差异。我们得出结论，CLP诱导的肝脏基因表达改变可能反映了IL-6活性的差异。
