TNF-α 及IL-1 分別在Concanavalin A 及酒精誘導的 急性肝炎所扮演之角色

Abstract

自體免疫性肝炎（autoimmune hepatitis, AIH）是一種慢性肝炎，好發於年輕女性，且可能進展為肝硬化。罹患自體免疫性肝炎時，患者的免疫系統會以肝臟細胞為攻擊對象，持續地破壞肝臟。目前對於造成自體免疫性肝炎的機制尚不清楚，本研究以 Con A 建立自體免疫肝炎的模式，探討 tumor necrosis factor-α (TNF-α)及 IL-1 (interleukin-1) 在自體免疫性肝炎扮演的機制。本研究結果發現，在TNF-α-/-、TNFR1-/- 及 IL-1R-/- 小鼠，嗜中性球進入肝組織的情形會減少，並且肝受損指數 ALT 有顯著下降。因此結果顯示，Con A 造成小鼠的肝損傷會透過TNF-α及 IL-1 的參與，吸引嗜中性球進入肝組織，造成肝組織受損。在本研究也發現在 TNF-α-/-及 TNFR1-/- 小鼠，CD4+ T 細胞浸潤肝臟組織會減少。因此 Con A 會透過 TNF-α 的參與，誘發 CD4+ T 細胞浸潤肝臟組織，進而造成肝臟的損傷。 酒精性肝炎引起的病理特徵有脂肪肝、發炎及肝細胞壞死。但對於酒精如何 引起肝臟受損的機制並不清楚。因此本研究建立急性酒精性肝炎的模式，探討其 可能的機制。研究中發現，在TNFR1 缺陷小鼠中，嗜中性球浸潤肝臟組織的情形 會減少，且肝受損指數 ALT 及 AST 有顯著下降。本研究的結果證實在酒精誘發 的急性肝損傷模式中 TNFα-TNFR1 之作用途徑參與嗜中性球浸潤肝臟組織，以及 造成肝組織受損情形。

Autoimmune hepatitis is a chronic inflammation in the liver that occurs when the body‘s immune system attacks the liver. Although the cause of autoimmune hepatitis is not entirely clear, some diseases, toxins and drugs may trigger autoimmune hepatitis insusceptible people, especially in women. Concanavalin A (Con A)-induced hepatitis in mice is thought to mimic autoimmune hepatitis in human. In this study, we investigated the role of TNF-α and IL-1 in Con A-induced hepatitis. We found that Con A-triggered serum ALT and AST production and neutrophil infiltration in liver were markedly reduced in TNF-α-/- mice, TNFR1-/- mice and IL-1R-/- mice. Furthermore, the number of CD4+ T cells in liver was also reduced in mice deficient of TNF-α, and TNFR1. Overall our findings imply that both TNF-α and IL-1 play important roles in mediating Con A-induced hepatitis by regulating the recruitment of neutrophils into liver. Although the histopathology of early alcoholic liver disease, i.e., steatosis,inflammation, and necrosis, has been well documented, the exact mechanisms of pathogenesis of this devastating disease are still unknown. In this study, we established the model of acute-alcohol hepatitis to investigate the role of TNF-α in ethanol-induced acute liver injury. We found that serum ALT levels in TNFR1-deficient mice were markedly reduced in alcohol-induced liver Injury. Neutrophil infiltration in alcohol-induced liver injury was also reduced in TNFR1-deficient mice. These results demonstrated that TNF-α was involved in alcohol-induced hepatitis by mediating the recruitment of neutrophils into liver.