Lake F R, Noble P W, Henson P M, Riches D W
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
J Clin Invest. 1994 Apr;93(4):1661-9. doi: 10.1172/JCI117148.
Recent work conducted in our laboratory has been directed towards understanding the role of TNF alpha in stimulating the synthesis of two macrophage gene products, namely IGF-1, a growth factor implicated in wound repair and fibrosis, and complement component factor B (Bf), an alternative pathway complement component. The expression of these proteins is induced by hyaluronic acid and poly (I:C), respectively, although TNF alpha plays a requisite role in the expression of both proteins. The objective of this study was to determine the mechanism governing the dichotomy in the expression of IGF-1 and Bf by TNF alpha. First, we questioned if the diversity in IGF-1 and Bf synthesis was regulated at the level of TNF receptor usage. Second, based on earlier findings that IFNs contribute to the initiation of Bf expression, we determined if IFNs modulate the response of macrophages to TNF alpha. Our data show that differences in TNF receptor usage cannot fully explain the dichotomy in the expression of IGF-1 and Bf. However, prior exposure to IFN-beta or IFN-gamma was found to be a dominant factor controlling the expression of these proteins, suppressing IGF-1, and enhancing Bf. These findings indicate that IFNs mediate a functional "switch" in the response of macrophages to TNF alpha and suggest that the pattern of cytokine expression by diverse macrophage stimuli is an important determinant of the eventual responses of macrophages to TNF alpha.
我们实验室最近开展的工作旨在了解肿瘤坏死因子α（TNFα）在刺激两种巨噬细胞基因产物合成中的作用，这两种产物分别是胰岛素样生长因子1（IGF-1），一种与伤口修复和纤维化有关的生长因子，以及补体成分B因子（Bf），一种替代途径补体成分。尽管TNFα在这两种蛋白质的表达中都起着必要作用，但这两种蛋白质的表达分别由透明质酸和聚肌苷酸-聚胞苷酸（poly (I:C)）诱导。本研究的目的是确定TNFα调控IGF-1和Bf表达二分法的机制。首先，我们质疑IGF-1和Bf合成的差异是否在TNF受体使用水平上受到调控。其次，基于早期发现干扰素有助于启动Bf表达，我们确定干扰素是否调节巨噬细胞对TNFα的反应。我们的数据表明，TNF受体使用的差异不能完全解释IGF-1和Bf表达的二分法。然而，发现预先暴露于干扰素-β或干扰素-γ是控制这些蛋白质表达的主要因素，它会抑制IGF-1并增强Bf。这些发现表明，干扰素介导巨噬细胞对TNFα反应中的功能性“开关”，并表明不同巨噬细胞刺激物引起的细胞因子表达模式是巨噬细胞最终对TNFα反应的重要决定因素。
