Retinoic acid stimulates the cell cycle machinery in normal T cells: Involvement of retinoic acid receptor-mediated IL-2 secretion
Retinoic acid stimulates the cell cycle machinery in normal T cells: Involvement of retinoic acid receptor-mediated IL-2 secretion
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DOI：
10.4049/jimmunol.169.10.5555
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发表时间：
2002-11-15
影响因子：
4.4
通讯作者：
Blomhow, HK
中科院分区：
文献类型：
--
作者：
Ertesvag, A;Engedal, N;Blomhow, HK
人们对维生素 A 刺激免疫系统的机制知之甚少。在当前的研究中，我们试图阐明全反式维甲酸（atRA）对人T淋巴细胞增殖的潜在作用机制。我们发现，当与常见的 T 细胞刺激剂联合添加时，生理水平的 atRA 可有效增强 T 细胞增殖。这反映在细胞周期机制的时间和浓度依赖性刺激上。 atRA 的存在导致细胞周期蛋白 D3、-E 和 -A 水平升高，p27 (Kip1) 水平降低，细胞周期蛋白依赖性激酶 2 活性增加，以及视网膜母细胞瘤蛋白 (pRB) 磷酸化增强。 atRA 介导的细胞周期机制变化是晚期事件，在刺激 20 小时后出现，表明 atRA 的影响是间接的。 atRA 不会改变高亲和力 IL-2R 的表达。然而，atRA 强烈增强了 T 细胞分泌的 IL-2 水平。 rIL-2能够替代atRA对细胞周期机制和DNA合成的影响，并且阻断IL-2R可显着抑制atRA诱导的细胞增殖和pRB磷酸化。视黄酸受体 (RAR) 选择性激动剂和 9-cis-RA 对 T 细胞增殖和 IL-2 分泌具有与 atRA 相同的效力，而类视黄酸 X 受体选择性激动剂仅具有边际效应。此外，RAR 选择性拮抗剂完全抑制了 atRA 诱导的 T 细胞增殖和 pRB 磷酸化。总而言之，这些结果表明 atRA 通过涉及 RAR 的机制增加 IL-2 分泌，从而刺激正常人 T 细胞的细胞周期机制和增殖。
The mechanisms whereby vitamin A stimulates the immune system are poorly understood. In the current study, we attempted to elucidate the potential mechanisms of action of all-trans retinoic acid (atRA) on proliferation of human T lymphocytes. We found that physiological levels of atRA potently augmented T cell proliferation when added in combination with common T cell-stimulating agents. This was reflected in a time- and concentration-dependent stimulation of the cell cycle machinery. The presence of atRA led to elevated levels of cyclin D3, -E, and -A, decreased levels of p27(Kip1), increased activity of cyclin-dependent kinase 2, and enhanced phosphorylation of the retinoblastoma protein (pRB). The atRA-mediated changes in the cell cycle machinery were late events, appearing after 20 h of stimulation, indicating that the effects of atRA were indirect. atRA did not alter the expression of the high-affinity IL-2R. However, the level of IL-2 secreted by T cells was strongly enhanced by atRA. rIL-2 was able to substitute for the effects of atRA on the cell cycle machinery and on DNA synthesis, and blocking the IL-2R markedly inhibited atRA-induced cell proliferation and pRB phosphorylation. A retinoic acid receptor (RAR)-selective agonist and, 9-cis-RA had the same potency as atRA on T cell proliferation and IL-2 secretion, whereas a retinoid X receptor-selective agonist had only marginal effects. Furthermore, a RAR-selective antagonist completely suppressed T cell proliferation and pRB phosphorylation induced by atRA. Taken together, these results suggest that atRA stimulates the cell cycle machinery and proliferation of normal human T cells by increasing IL-2 secretion through mechanisms involving RARs.