Donnelly R P, Crofford L J, Freeman S L, Buras J, Remmers E, Wilder R L, Fenton M J
Division of Cytokine Biology, FDA, Bethesda, MD 20892.
J Immunol. 1993 Nov 15;151(10):5603-12.
IL-4 inhibits production of certain proinflammatory cytokines, including IL-1 beta, TNF-alpha, and IL-6, by activated monocytes. Although monocytes are a major source of IL-6, other cell types such as fibroblasts and endothelial cells can also express this cytokine. To determine whether IL-4 inhibits IL-6 expression in non-hemopoietic cells, we investigated the effects of IL-4 on IL-6 production in both primary human fibroblasts and fibroblast lines. Rheumatoid synovial fibroblasts were evaluated in these studies because, like monocytes, they produce high levels of IL-6 when stimulated with IL-1. Although peripheral blood monocytes did not constitutively express IL-6 mRNA or protein, stimulation with IL-1 or LPS induced de novo IL-6 expression in these cells. In contrast, synovial fibroblasts displayed a significant basal level of IL-6 production, which was markedly increased after stimulation with IL-1. IL-4 suppressed IL-6 expression in monocytes, but did not inhibit IL-6 production in synovial fibroblasts. The inability of IL-4 to suppress IL-6 synthesis in rheumatoid synovial fibroblasts was not caused by a lack of IL-4R and was not unique to these cells because IL-4 also failed to inhibit IL-6 production in normal fibroblast lines derived from other tissues. Inhibition of IL-6 production by IL-4 in monocytes was associated with decreased nuclear NF-kappa B levels. However, IL-4 does not globally suppress the activity of all DNA-binding proteins because IL-4 treatment did not reduce the levels of NF-IL-6 or NF-IL-1 beta B in the same cells. Because NF-kappa B activation is required for transcription of many cytokine genes, including IL-6, the ability of IL-4 to suppress NF-kappa B activity in monocytes suggests a potential mechanism by which this molecule may inhibit the expression of multiple cytokines.
白细胞介素-4（IL-4）可抑制活化单核细胞产生某些促炎细胞因子，包括白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）。虽然单核细胞是IL-6的主要来源，但其他细胞类型，如成纤维细胞和内皮细胞也可表达这种细胞因子。为了确定IL-4是否抑制非造血细胞中IL-6的表达，我们研究了IL-4对原代人成纤维细胞和成纤维细胞系中IL-6产生的影响。在这些研究中对类风湿性滑膜成纤维细胞进行了评估，因为与单核细胞一样，它们在受到IL-1刺激时会产生高水平的IL-6。虽然外周血单核细胞不组成性表达IL-6 mRNA或蛋白，但用IL-1或脂多糖（LPS）刺激可诱导这些细胞从头表达IL-6。相反，滑膜成纤维细胞显示出显著的基础水平IL-6产生，在用IL-1刺激后明显增加。IL-4抑制单核细胞中IL-6的表达，但不抑制滑膜成纤维细胞中IL-6的产生。IL-4无法抑制类风湿性滑膜成纤维细胞中IL-6的合成，这不是由于缺乏IL-4受体所致，并且并非这些细胞所特有，因为IL-4也无法抑制源自其他组织的正常成纤维细胞系中IL-6的产生。IL-4对单核细胞中IL-6产生的抑制与细胞核中核因子-κB（NF-κB）水平降低有关。然而，IL-4并不会全面抑制所有DNA结合蛋白的活性，因为IL-4处理并未降低同一细胞中NF-IL-6或NF-IL-1βB的水平。由于NF-κB活化是许多细胞因子基因（包括IL-6）转录所必需的，IL-4抑制单核细胞中NF-κB活性的能力提示了该分子可能抑制多种细胞因子表达的潜在机制。
