Villiger P M, Geng Y, Lotz M
Sam and Rose Stein Institute for Research in Aging, University of California, San Diego, La Jolla 92093.
J Clin Invest. 1993 Apr;91(4):1575-81. doi: 10.1172/JCI116363.
Biological effects of cytokines are in part determined by their interactions in the regulation of cytokine production. This study analyzes the effects of leukemia inhibitory factor (LIF) on cytokine expression in different cell lineages. Recombinant human LIF increases levels of IL-1 beta, IL-6, and IL-8 mRNA in human articular chondrocytes as demonstrated by Northern blotting. These cytokine mRNAs are detectable as early as 1.3 h after stimulation and reach their maximum after 5 h. The LIF effects are dose dependent and of similar magnitude to those of IL-1. By metabolic labeling and immunoprecipitation it is shown that LIF induces synthesis and secretion of IL-6. IL-6 bioactivity in conditioned media, as measured by the B9 hybridoma proliferation assay, is increased by LIF. Effects of LIF on cytokine expression are not confined to connective tissue cells. By PCR it is shown that human blood monocytes express IL-6 mRNA after stimulation with LIF. An increase in IL-6 mRNA levels is detectable 2 h after stimulation, and this starts to decline by 5 h. The response is of shorter duration as compared with IL-1 beta. In addition to increased mRNA expression, LIF also stimulates release of biologically active IL-6 from blood monocytes. In synoviocytes and neuronal as well as epithelial cell lines, LIF increases IL-1 beta and IL-6 gene expression. In summary, LIF induces cytokine expression in a wide variety of tissues. These results suggest that through the induction of cytokines, LIF can modulate inflammation, immune responses, and connective tissue metabolism, and act as a pathogenetic mediator in different disease states.
细胞因子的生物学效应部分取决于它们在细胞因子产生调节中的相互作用。本研究分析了白血病抑制因子（LIF）对不同细胞谱系中细胞因子表达的影响。Northern印迹法显示，重组人LIF可增加人关节软骨细胞中IL-1β、IL-6和IL-8 mRNA的水平。这些细胞因子mRNA在刺激后1.3小时即可检测到，并在5小时后达到最大值。LIF的作用具有剂量依赖性，且与IL-1的作用强度相似。通过代谢标记和免疫沉淀法表明，LIF可诱导IL-6的合成和分泌。通过B9杂交瘤增殖试验测定，条件培养基中的IL-6生物活性因LIF而增加。LIF对细胞因子表达的影响并不局限于结缔组织细胞。通过PCR表明，人血单核细胞在LIF刺激后表达IL-6 mRNA。刺激后2小时可检测到IL-6 mRNA水平升高，并在5小时开始下降。与IL-1β相比，该反应持续时间较短。除了增加mRNA表达外，LIF还刺激血单核细胞释放具有生物活性的IL-6。在滑膜细胞、神经元以及上皮细胞系中，LIF可增加IL-1β和IL-6基因表达。总之，LIF可在多种组织中诱导细胞因子表达。这些结果表明，通过诱导细胞因子，LIF可调节炎症、免疫反应和结缔组织代谢，并在不同疾病状态下作为致病介质发挥作用。
