TISSUE SPECIFIC REGULATION OF CYTOKINE PRODUCTION BY IL-4

IL-4抑制某些促炎细胞因子的产生，包括 IL-1a、TNF-α和IL-6，通过单核细胞活化。尽管单核细胞 IL-6的主要来源，其他类型的细胞，如成纤维细胞和 内皮细胞，也可以表达这种细胞因子。以确定是否 IL-4抑制非造血细胞中细胞因子的表达 研究了IL-4对两种原发人体产生IL-6的影响 成纤维细胞和成纤维细胞系。类风湿滑膜成纤维细胞 在这些研究中进行评估是因为，像单核细胞一样，它们产生高水平的 IL-1刺激时的IL-6水平。虽然外周血液 单核细胞不表达IL-6mRNA或蛋白， IL-1或内毒素刺激诱导人脐静脉内皮细胞IL-6从头表达 细胞。相反，滑膜成纤维细胞表现出显著的基础 IL-6的产生水平在以下情况下显著增加 用IL-1刺激。IL-4抑制单核细胞IL-6的表达，但 不抑制滑膜成纤维细胞产生IL-6。无能为力 IL-4抑制类风湿滑膜成纤维细胞合成IL-6的实验研究 不是继发于IL-4受体的缺乏，也不是独有的 这些细胞因为IL-4也不能抑制正常人体内IL-6的产生 来源于其他组织的成纤维细胞系。IL-6的抑制作用 单核细胞产生IL-4与核抑制相关 因子-kappaB(NF-kB)活性。然而，IL-4并不能降低 其他核因子包括核因子-IL-6、核因子-IL-1B和AP-1的水平 单核细胞或成纤维细胞。因为需要激活核因子-kB 对于包括IL-6在内的许多促炎细胞因子基因的转录， IL-4抑制单核细胞核因子-kB活性的能力表明 该分子可能通过其抑制基因表达的潜在机制 多种细胞因子。

IL-4 inhibits production of certain proinflammatory cytokines, including IL-1a, TNF-a 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 cytokine expression in non-hematopoietic 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 following 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 secondary to an absence of IL-4 receptors, 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 correlated with suppression of nuclear factor-kappa B (NF-kB) activity. However, IL-4 did not decrease the levels of other nuclear factors, including NF-IL6, NF-IL-1B and AP-1 in either monocytes or fibroblasts. Because NF-kB activation is required for transcription of many proinflammatory cytokine genes, including IL-6, the ability of IL-4 to suppress NF-kB activity in monocytes suggests a potential mechanism by which this molecule may inhibit the expression of multiple cytokines.