McKarns S C, Kaminski N E
Department of Pharmacology and Toxicology, B330 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317, USA.
Immunopharmacology. 2000 Jul 20;48(2):101-15. doi: 10.1016/s0162-3109(00)00183-1.
Transforming growth factor-beta(1) (TGF-beta(1)) is a critical bifunctional regulator of inflammatory responses. Evidence strongly suggests that these regulatory consequences are, at least in part, a result of profound pleiotropic effects on T lymphocyte effector function. The mechanisms underlying the contradictory biological effects of TGF-beta(1) remain ambiguous. The objective of the present studies was to test the hypothesis that the concentration of TGF-beta(1) and the temporal relationship between activation of the T cell receptor (TCR) and the TGF-beta receptor regulate the effect of TGF-beta(1) on T lymphocyte activation and proliferation. Toward this end, we have quantified the concentration- and time-dependent effect of TGF-beta(1) on interleukin-2 (IL-2) protein secretion as an index of T lymphocyte activation and [3H]-thymidine incorporation as an index of cell proliferation in primary splenocytes and thymocytes. Our results suggest that TGF-beta(1) stimulates IL-2 production at low concentrations (0.1-1 pg/ml) and conversely inhibits IL-2 production at high concentrations (1-10 ng/ml) in CD3epsilon monoclonal antibody (mAb)+/-CD28 mAb-activated splenocytes. Additionally, concentrations of TGF-beta(1) that stimulate IL-2 production in CD3epsilon mAb+CD28 mAb-activated splenocytes concominantly inhibit splenocyte proliferation under similar conditions. Furthermore, we provide evidence suggesting that the effects of TGF-beta(1) on T lymphocytes are dependent upon the temporal relationship between activation of the TCR and the TGF-beta receptor. A time-dependent loss of a stimulatory effect and a concomitant gain of an inhibitory response by TGF-beta(1) on IL-2 production in response to CD3epsilon and CD28 mAbs is observed when TGF-beta(1) is added following T lymphocyte activation. In summary, these data unequivocally demonstrate that the orchestration of paradoxical effects of TGF-beta(1) on T-lymphocyte function is dependent upon the concentration of TGF-beta(1) and the temporal relationship between activation of signaling through the TCR and the TGF-beta receptor. Future mechanistic studies addressing the putative role that these factors play in modulating the effects of TGF-beta(1) on T lymphocyte activity will undoubtedly provide valuable insight towards the pharmacological intervention of inflammatory responses.
转化生长因子-β(1)（TGF-β(1)）是炎症反应的关键双功能调节因子。有力证据表明，这些调节作用至少部分是对T淋巴细胞效应功能产生深刻多效性影响的结果。TGF-β(1)矛盾生物学效应的潜在机制仍不明确。本研究的目的是检验以下假设：TGF-β(1)的浓度以及T细胞受体（TCR）激活与TGF-β受体激活之间的时间关系调节TGF-β(1)对T淋巴细胞激活和增殖的作用。为此，我们已量化了TGF-β(1)对白细胞介素-2（IL-2）蛋白分泌（作为T淋巴细胞激活指标）以及[3H]-胸腺嘧啶核苷掺入（作为原代脾细胞和胸腺细胞中细胞增殖指标）的浓度和时间依赖性效应。我们的结果表明，在CD3ε单克隆抗体（mAb）+/-CD28 mAb激活的脾细胞中，低浓度（0.1 - 1 pg/ml）的TGF-β(1)刺激IL-2产生，相反，高浓度（1 - 10 ng/ml）则抑制IL-2产生。此外，在类似条件下，刺激CD3ε mAb + CD28 mAb激活的脾细胞中IL-2产生的TGF-β(1)浓度同时抑制脾细胞增殖。此外，我们提供的证据表明，TGF-β(1)对T淋巴细胞的作用取决于TCR激活与TGF-β受体激活之间的时间关系。当在T淋巴细胞激活后添加TGF-β(1)时，观察到TGF-β(1)对CD3ε和CD28 mAbs刺激的IL-2产生的刺激作用随时间丧失，同时抑制反应增强。总之，这些数据明确表明，TGF-β(1)对T淋巴细胞功能的矛盾效应的调控取决于TGF-β(1)的浓度以及通过TCR和TGF-β受体的信号激活之间的时间关系。未来针对这些因素在调节TGF-β(1)对T淋巴细胞活性作用中所起假定作用的机制研究，无疑将为炎症反应的药理学干预提供有价值的见解。
