Tipton D A, Pabst M J, Dabbous M K
Dental Research Center, University of Tennessee, Memphis 38163.
J Cell Biochem. 1990 Dec;44(4):253-64. doi: 10.1002/jcb.240440407.
To investigate the mechanism of cyclosporine (Cs)-induced fibrous gingival enlargement, the indirect effects of Cs on fibroblast collagenolysis via the drug's effect on the synthesis of the fibroblast regulatory monokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) have been studied. Peripheral blood monocytes stimulated with lipopolysaccharide (LPS) for 48 h produced conditioned media (MCM-LPS) that contained 665 pg/ml IL-1 beta and 16 pg/ml TNF alpha and significantly (P less than 0.001) enhanced the collagenase activity of a fibroblast strain (GN 23) derived from a healthy individual with clinically normal gingiva. The concurrent addition of Cs (50, 100, or 150 ng/ml) with LPS to the monocytes (MCM-LPS-Cs) significantly diminished their ability to enhance GN 23 collagenase activity in a dose-dependent manner, with MCM-LPS-Cs (150 ng/ml) causing the greatest effect. Cs also significantly inhibited IL-1 beta and TNF alpha production. Although the greatest inhibition of both cytokines was at 50 ng/ml Cs, the corresponding MCM-LPS-Cs caused the least diminution (16%) of the collagenase stimulation caused by MCM-LPS (no Cs). This suggested that factor(s) other than or in addition to IL-1 beta and TNF alpha might be responsible for the stimulation of GN 23 collagenase activity. MCM-LPS depleted of IL-1 beta by affinity chromatography retained its stimulatory effect on GN 23 collagenolysis, and human recombinant IL-1 beta and TNF alpha, when tested alone or together at levels found in the stimulatory MCM-LPS and MCM-LPS-Cs, did not stimulate GN 23 collagenase activity as did the crude conditioned media. This evidence suggested that the conditioned media contained the complex mixture of cytokines necessary to stimulate collagenase activity of this fibroblast strain and that IL-1 beta and TNF alpha were not necessarily involved. Cs may alter the synthesis of other collagenase-stimulating cytokines, accounting for the diminished ability of Cs-treated monocytes to enhance collagenase activity of susceptible fibroblast strains. Decreased collagenase activity, therefore, resulting from Cs suppression of monokine production, may be an important factor in the development of fibrous gingival enlargement seen in some susceptible patients treated with Cs.
为研究环孢素（Cs）诱导纤维性牙龈增生的机制，通过Cs对成纤维细胞调节性单核因子白细胞介素-1β（IL-1β）和肿瘤坏死因子-α（TNFα）合成的影响，研究了Cs对成纤维细胞胶原溶解的间接作用。用脂多糖（LPS）刺激外周血单核细胞48小时，产生的条件培养基（MCM-LPS）含有665 pg/ml的IL-1β和16 pg/ml的TNFα，并显著（P<0.001）增强了源自临床牙龈正常的健康个体的成纤维细胞系（GN 23）的胶原酶活性。将Cs（50、100或150 ng/ml）与LPS同时添加到单核细胞中（MCM-LPS-Cs），以剂量依赖的方式显著降低了它们增强GN 23胶原酶活性的能力，其中MCM-LPS-Cs（150 ng/ml）的作用最大。Cs还显著抑制IL-1β和TNFα的产生。尽管在50 ng/ml Cs时对两种细胞因子的抑制作用最大，但相应的MCM-LPS-Cs对MCM-LPS（无Cs）引起的胶原酶刺激的减弱作用最小（16%）。这表明除IL-1β和TNFα之外或与之相关的其他因子可能是刺激GN 23胶原酶活性的原因。通过亲和层析去除IL-1β的MCM-LPS对GN 23胶原溶解仍具有刺激作用，并且人重组IL-1β和TNFα在单独或一起以刺激MCM-LPS和MCM-LPS-Cs中发现的水平进行测试时，并未像粗制条件培养基那样刺激GN 23胶原酶活性。该证据表明条件培养基含有刺激该成纤维细胞系胶原酶活性所需的细胞因子复杂混合物，并且IL-1β和TNFα不一定参与其中。Cs可能会改变其他刺激胶原酶的细胞因子的合成，这解释了经Cs处理的单核细胞增强易感成纤维细胞系胶原酶活性的能力减弱的原因。因此，由于Cs抑制单核因子产生导致的胶原酶活性降低，可能是在用Cs治疗的一些易感患者中出现纤维性牙龈增生的一个重要因素。
