Circolo A, Welgus H G, Pierce G F, Kramer J, Strunk R C
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
J Biol Chem. 1991 Jul 5;266(19):12283-8.
We have previously reported that polypeptide growth factors had an anti-inflammatory effect by decreasing the cytokine-enhanced expression of factor B (FB), an activator of the alternative complement pathway, in human fibroblasts. To further characterize the role of cytokines and growth factors in the inflammatory/repair continuum, we have studied the effects of interleukin-1 (IL-1) and platelet-derived growth factor (PDGF) on the expression of metalloproteinases/antiproteinases of the extracellular matrix in cultured human fibroblasts. Co-incubation of IL-1 and PDGF synergistically increased the expression of stromelysin and interstitial collagenase to 23-fold (for both proteins) over background, while PDGF decreased the IL-1-enhanced expression of FB by 82%. PDGF, but not IL-1, alone or in combination, increased the synthesis of tissue inhibitor of metalloproteinases. RNA blot analysis indicated that the changes in protein synthesis were regulated at a pretranslational level. Cycloheximide treatment indicated that the effects of PDGF on the metalloproteinases/antiproteinases were not protein-dependent, in contrast to results obtained for FB. The effect of the three dimeric forms of PDGF (AA, AB, and BB) on the synthesis of metalloproteinases and FB was also analyzed. The effects were qualitatively similar for each of the dimeric forms; however, the BB and AB isoforms had considerably greater effects than PDGF-AA. It has been reported that the PDGF receptors found in human fibroblasts have higher binding affinity for the BB and AB isoforms of the growth factor. The results presented in this paper are in accord with the possibility that differences in the biological activity of the three isoforms of PDGF are due to differences in the number or affinity of the binding sites of the target cells, rather than to different activation pathways of the receptor. Thus, PDGF increased cytokine effects on metalloproteinases, while decreasing cytokine effects or complement activator FB. The net effect of these changes may be to decrease inflammation and enhance remodeling early in repair and to enhance matrix stability later in the repair process.
我们之前曾报道，多肽生长因子可通过降低人成纤维细胞中替代补体途径激活因子B（FB）的细胞因子增强表达来发挥抗炎作用。为了进一步明确细胞因子和生长因子在炎症/修复连续过程中的作用，我们研究了白细胞介素-1（IL-1）和血小板衍生生长因子（PDGF）对培养的人成纤维细胞中细胞外基质金属蛋白酶/抗蛋白酶表达的影响。IL-1和PDGF共同孵育可协同将基质溶素和间质胶原酶的表达提高至比基础水平高23倍（两种蛋白均如此），而PDGF可使IL-1增强的FB表达降低82%。单独或联合使用时，PDGF而非IL-1可增加金属蛋白酶组织抑制剂的合成。RNA印迹分析表明，蛋白质合成的变化在翻译前水平受到调控。环己酰亚胺处理表明，与FB的结果相反，PDGF对金属蛋白酶/抗蛋白酶的作用不依赖于蛋白质。我们还分析了PDGF的三种二聚体形式（AA、AB和BB）对金属蛋白酶和FB合成的影响。每种二聚体形式的作用在性质上相似；然而，BB和AB异构体的作用比PDGF-AA大得多。据报道，在人成纤维细胞中发现的PDGF受体对生长因子的BB和AB异构体具有更高的结合亲和力。本文呈现的结果符合以下可能性，即PDGF三种异构体的生物活性差异是由于靶细胞结合位点数量或亲和力的差异，而非受体的不同激活途径。因此，PDGF增强了细胞因子对金属蛋白酶的作用，同时降低了细胞因子的作用或补体激活剂FB。这些变化的净效应可能是在修复早期减轻炎症并增强重塑，在修复后期增强基质稳定性。
