Linner K M, Quist H E, Sharp B M
Minneapolis Medical Research Foundation, MN 55404, USA.
J Immunol. 1995 May 15;154(10):5049-60.
Murine thymocytes activated with the mitogen Con A express proenkephalin A mRNA (PEA mRNA) and met-enkephalin and/or met-enkephalin-containing peptides ("enkephalins"). This Con A-induced expression of PEA mRNA is modulated by the delta opioid receptor agonist, deltorphin I, in a biphasic, dose-dependent manner. That is, 10(-13) M to 10(-11) M deltorphin enhanced PEA mRNA expression 3- to 3.5-fold over the level induced by Con A alone, and 10(-9) M to 10(-7) M deltorphin inhibited it 40 to 70%. delta opioid receptor antagonists recognizing the delta-2 (naltrindole (NTI) and naltriben (NTB)), but not the delta-1 (7-benzylidenenaltrexone (BNTX)), subtype of opioid receptor described in brain, reversed both the enhancing and inhibiting effects of deltorphin on Con A-induced PEA mRNA expression. In addition, the delta-2 receptor-specific antagonists, NTI and NTB, directly inhibited Con A-induced PEA mRNA expression. The function of the enkephalins expressed by thymocytes was examined by using 1) delta opioid receptor antagonists, 2) PEA mRNA-specific antisense cDNA, and 3) Ab to met-enkephalin, and measuring cell proliferation. All three reagents caused enhancement of Con A-induced proliferation, with effects ranging from two- to fourfold over the response to Con A alone. Again, the delta-2 subtype-specific antagonists, NTI and NTB, were functional and the delta-1 subtype-specific antagonist, BNTX, was not. The PEA mRNA-specific antisense cDNA blocked translation but not transcription of PEA mRNA. The data suggest that 1) endogenous enkephalins induced in thymocytes modulate their own expression through delta-2-like opioid receptors, and 2) these endogenous enkephalins function to inhibit the proliferation of activated thymocytes.
用促细胞分裂剂刀豆球蛋白A激活的小鼠胸腺细胞表达前脑啡肽A信使核糖核酸（PEA信使核糖核酸）以及甲硫氨酸脑啡肽和/或含甲硫氨酸脑啡肽的肽（“脑啡肽”）。刀豆球蛋白A诱导的PEA信使核糖核酸的这种表达受到δ阿片受体激动剂德尔托啡肽I的双相、剂量依赖性调节。也就是说，10^(-13)M至10^(-11)M的德尔托啡肽使PEA信使核糖核酸的表达比单独由刀豆球蛋白A诱导的水平提高了3至3.5倍，而10^(-9)M至10^(-7)M的德尔托啡肽则抑制了40%至70%。识别脑中描述的阿片受体δ-2亚型（纳曲吲哚（NTI）和纳曲苄（NTB））而非δ-1亚型（7-苄叉基纳曲酮（BNTX））的δ阿片受体拮抗剂，逆转了德尔托啡肽对刀豆球蛋白A诱导的PEA信使核糖核酸表达的增强和抑制作用。此外，δ-2受体特异性拮抗剂NTI和NTB直接抑制刀豆球蛋白A诱导的PEA信使核糖核酸表达。通过使用1）δ阿片受体拮抗剂、2）PEA信使核糖核酸特异性反义互补脱氧核糖核酸和3）抗甲硫氨酸脑啡肽抗体并测量细胞增殖，研究了胸腺细胞表达的脑啡肽的功能。所有这三种试剂都导致刀豆球蛋白A诱导的增殖增强，其效果比单独对刀豆球蛋白A的反应高出两到四倍。同样，δ-2亚型特异性拮抗剂NTI和NTB具有功能，而δ-1亚型特异性拮抗剂BNTX则没有。PEA信使核糖核酸特异性反义互补脱氧核糖核酸阻断了PEA信使核糖核酸的翻译但未阻断其转录。数据表明：1）胸腺细胞中诱导产生的内源性脑啡肽通过δ-2样阿片受体调节其自身的表达；2）这些内源性脑啡肽的功能是抑制活化胸腺细胞的增殖。
