HEPATIC GENE EXPRESSION AND CYTOKINE RESPONSES TO STERILE INFLAMMATION

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Abstract
Inflammatory stimulation of hepatic acute phase protein expression is, in part, modulated by tumor necrosis factor-± (TNF±), interleukin-1/± (IL-1/±), 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 TNF ±/IL-1/± 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 TNF ±/IL-1±-regulated ±1--acid glycoprotein, and IL-6–regulated ±2--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 TNF ±/IL-1±-linked transcription factor NF-±B and the intrahepatic abundance of TNF± 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.

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