Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Hepatology. 2011 Feb;53(2):649-60. doi: 10.1002/hep.24059. Epub 2011 Jan 10.
Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow-specific IRF3-KO mice, deficiency of IRF3 only in parenchymal cells aggravated alcohol-induced liver injury, associated with increased proinflammatory cytokines, lower antiinflammatory cytokine interleukin 10 (IL-10), and lower Type I IFNs compared to WT mice. Coculture of WT primary murine hepatocytes with liver mononuclear cells (LMNC) resulted in higher LPS-induced IL-10 and IFN-β, and lower tumor necrosis factor alpha (TNF-α) levels compared to LMNC alone. Type I IFN was important because cocultures of hepatocytes with LMNC from Type I IFN receptor KO mice showed attenuated IL-10 levels compared to control cocultures from WT mice. We further identified that Type I IFNs potentiated LPS-induced IL-10 and inhibited inflammatory cytokine production in both murine macrophages and human leukocytes, indicating preserved cross-species effects. These findings suggest that liver parenchymal cells are the dominant source of Type I IFN in a TLR4/IRF3-dependent manner. Further, parenchymal cell-derived Type I IFNs increase antiinflammatory and suppress proinflammatory cytokines production by LMNC in paracrine manner.
Our results indicate that IRF3 activation in parenchymal cells and resulting type I IFNs have protective effects in ALD by way of modulation of inflammatory functions in macrophages. These results suggest potential therapeutic targets in ALD.
酒精性肝病（ALD）的特征是肝内暴露于细菌脂多糖（LPS）增加。Toll 样受体 4（TLR4）识别 LPS 并根据 MyD88 或 TRIF 衔接蛋白激活信号通路。我们之前表明，MyD88 在 ALD 中是可有可无的。TLR4 以依赖干扰素调节因子 3（IRF3）的 MyD88 非依赖性方式诱导 I 型干扰素（IFN）。我们用酒精或对照饮食喂养野生型（WT）和干扰素调节因子 3 敲除（KO）小鼠，以及肝脏实质细胞和骨髓来源细胞中选择性 IRF3 缺陷的小鼠。全身 IRF3-KO 小鼠免受酒精引起的肝损伤、脂肪变性和炎症的影响。与 WT 或骨髓特异性 IRF3-KO 小鼠相比，仅在实质细胞中缺乏 IRF3 会加重酒精引起的肝损伤，与 WT 小鼠相比，促炎细胞因子增加，抗炎细胞因子白细胞介素 10（IL-10）降低，I 型 IFN 降低。与单独的肝单核细胞（LMNC）相比，WT 原代小鼠肝细胞与 LMNC 的共培养导致 LPS 诱导的 IL-10 和 IFN-β增加，肿瘤坏死因子-α（TNF-α）水平降低。I 型 IFN 很重要，因为与来自 WT 小鼠的对照共培养物相比，肝细胞与 I 型 IFN 受体 KO 小鼠的 LMNC 的共培养物显示出降低的 IL-10 水平。我们进一步确定 I 型 IFN 增强了 LPS 诱导的 IL-10，并抑制了小鼠巨噬细胞和人白细胞中的炎症细胞因子产生，表明保留了种间效应。这些发现表明，TLR4/IRF3 依赖性方式下，肝实质细胞是 I 型 IFN 的主要来源。此外，实质细胞衍生的 I 型 IFN 通过旁分泌方式增加 LMNC 中抗炎和抑制促炎细胞因子的产生。
我们的结果表明，IRF3 在实质细胞中的激活和由此产生的 I 型 IFN 通过调节巨噬细胞中的炎症功能，对 ALD 具有保护作用。这些结果表明 ALD 中有潜在的治疗靶点。
