Circolo A, Pierce G F, Katz Y, Strunk R C
Division of Pulmonary Medicine, St. Louis Children's Hospital, Missouri.
J Biol Chem. 1990 Mar 25;265(9):5066-71.
The synthesis of complement components in human fibroblasts is modulated by mediators of inflammation such as cytokines. In particular, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce time- and dose-dependent increases in the synthesis of complement proteins factor B (FB), C3, and factor H (FH). Polypeptide growth factors are also soluble mediators released during inflammation and able to modulate many fibroblast functions. We have studied the effects of polypeptide growth factors platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) on the synthesis of complement proteins in cultured human fibroblasts. PDGF, EGF, and FGF alone did not affect the level of synthesis of any of the complement proteins analyzed, but simultaneous incubation of PDGF, EGF, or FGF with IL-1 and TNF resulted in a dose-dependent inhibition of the cytokine-enhanced expression of FB. Inhibition of FB synthesis was observed between 4 and 8 h of exposure to PDGF and persisted for 4 h after the removal of the growth factor. Analysis of steady-state levels of specific FB mRNA suggested that PDGF-induced inhibition of FB synthesis is mediated at a pretranslational level and that it requires new protein synthesis. The effect of the growth factors was limited to FB, with marginal or no inhibition on the cytokine-enhanced synthesis of C3 and FH, excluding the possibility that the inhibitory effects of PDGF, EGF, and FGF on FB synthesis were due to a negative modulation of the growth factors on cytokine cell membrane receptors. Specific inhibition of cytokine-induced increases in FB synthesis by the growth factors may represent down regulation of the acute inflammatory process, further permitting progression to processes of tissue repair and remodeling. Study of the interactions between cytokines and growth factors in the regulation of synthesis of complement proteins may also provide a system for investigating mechanisms of signal transduction of both polypeptide growth factors and cytokines.
人类成纤维细胞中补体成分的合成受细胞因子等炎症介质的调节。特别是，白细胞介素 -1（IL -1）和肿瘤坏死因子（TNF）可诱导补体蛋白B因子（FB）、C3和H因子（FH）的合成呈现时间和剂量依赖性增加。多肽生长因子也是炎症过程中释放的可溶性介质，能够调节多种成纤维细胞功能。我们研究了血小板衍生生长因子（PDGF）、表皮生长因子（EGF）和成纤维细胞生长因子（FGF）等多肽生长因子对培养的人类成纤维细胞中补体蛋白合成的影响。单独的PDGF、EGF和FGF均不影响所分析的任何补体蛋白的合成水平，但将PDGF、EGF或FGF与IL -1和TNF同时孵育会导致细胞因子增强的FB表达出现剂量依赖性抑制。在暴露于PDGF的4至8小时之间观察到FB合成受到抑制，并且在去除生长因子后持续4小时。对特定FB mRNA稳态水平的分析表明，PDGF诱导的FB合成抑制是在翻译前水平介导的，并且需要新的蛋白质合成。生长因子的作用仅限于FB，对细胞因子增强的C3和FH合成仅有轻微抑制或无抑制，排除了PDGF、EGF和FGF对FB合成的抑制作用是由于生长因子对细胞因子细胞膜受体的负调节所致的可能性。生长因子对细胞因子诱导的FB合成增加的特异性抑制可能代表急性炎症过程的下调，进一步促进组织修复和重塑过程的进展。研究细胞因子与生长因子在补体蛋白合成调节中的相互作用也可能为研究多肽生长因子和细胞因子的信号转导机制提供一个系统。
