Bogdan C, Paik J, Vodovotz Y, Nathan C
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
J Biol Chem. 1992 Nov 15;267(32):23301-8.
Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
转化生长因子（TGF）-β和白细胞介素（IL）-10通过不同的转录后机制抑制脂多糖（LPS）诱导的巨噬细胞产生炎性细胞因子肿瘤坏死因子-α（TNF）、IL-1α和IL-1β。TGF-β作用缓慢且较迟，因为它需要12 - 16小时才能发挥抑制作用，甚至在LPS加入6小时后添加仍能抑制TNF产生。TGF-β既不影响TNF mRNA水平、预先形成的TNF释放，也不影响TNF的降解。因此，TGF-β似乎抑制TNF mRNA的翻译。IL-10不仅比TGF-β更有效地抑制TNF释放达25倍之多，还抑制IL-1的释放。与TGF-β不同，IL-10作用于细胞因子产生的早期阶段，在加入LPS后3小时其作用达到最大。与TGF-β不同，IL-10显著抑制TNF、IL-1α和IL-1β的mRNA水平。然而，这是在不抑制相应基因转录的情况下实现的。此外，放线菌酮拮抗IL-10依赖的细胞因子mRNA水平降低。因此，IL-10可能诱导一种对细胞因子转录本有活性的核糖核酸酶，或者诱导一种增强TNF、IL-1α和IL-1β mRNA对核糖核酸酶作用敏感性的蛋白质。我们得出结论：IL-10和TGF-β诱导巨噬细胞失活的不同表型，并通过不同机制使巨噬细胞失活：IL-10促进细胞因子mRNA的降解，而TGF-β主要抑制翻译。
