CHRONOBIOLOGICAL INVESTIGATION OF TNF AND IL-2

TNF 和 IL-2 的时间生物学研究

• 批准号: 3195410
• 负责人: WILLIAM JM HRUSHESKY
• 金额: $ 9.62万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-06 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3195410
• 关键词: albino mouse; animal population study; antineoplastic antibiotics; cellular immunity; chronotherapy; circadian rhythms; drug adverse effect; immunopharmacology; interleukin 2; metastasis; neoplasm /cancer immunotherapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; pituitary adrenal axis; seasons; sex cycle; tumor necrosis factor alpha

It is proposed to investigate the circadian stage dependency of the toxicities, biologic activities and anticancer activities of recombinant human Tumor Necrosis Factor (rhTNF) and Interleukin 2 (rhIL-2) in the Balb/c mouse with and without an implanted Meth-A sarcoma. We have found preliminarily that the circadian time and season of tumor inoculation affect both tumor take rate and natural killer cell activity. We have also found that the timing of tumor resection within the fertility cycle affects the frequency of subsequent metastatic tumor spread and that the fertility cycle affects the level of immunocyte NK activity. Therefore, the effects of female fertility cycle stage and season at time of study will also be quantified. The biological effects of most, if not all, trophic hormones are dependent to some extent upon the temporal patterning of their release or administra- tion. Fertility depends upon the pulsatility of FSH and LH delivery from the pituitary to the ovary and testis. Cortisol release depends intimately upon both the high frequency pulsing and the circadian patterning of ACTH delivery from the pituitary to the adrenal glands. IL-1 is a centrally positioned cytokine having synergistic activities with TNF and interactive or stimulatory effects upon several other cytokines and growth factors. Glucocorticoids (which are exquisitely circadian rhythmic) modulate the dynamics of IL-1 gene transcription rate, messenger RNA stability and resultant translation rate and IL-1 cellular release rate, as well as TNF- induced cytotoxicity. IL-1, in turn, modulates glucocorticoid receptor binding, decreases available binding sites and reduces steroid-associated enzyme induction. These steroid/cytokine interactions suggest that chronobiologic investigation of cytokine toxicity and anticancer efficacy may be important. The toxic and therapeutic anticancer effects of many cytotoxic xenobiotic anticancer agents depend upon their circadian timing. Reproducible peak- trough circadian differences in toxicity and anticancer activity usually range between 50% and 250%. Preliminary data on tumor necrosis factor indicate that the circadian stage dependent differences in toxic/therapeut- ic ratio may be of substantially higher magnitude for cytokines. Specific hypotheses to be addressed by the proposed research include: 1) Endogenous, reproducible, nontrivial and quantifiable circadian rhythms ( which are reproducibly modulated by both the fertility cycle and season) characterize (murine and human) normal biology; 2) Population synchrony, gauged by reference to sleep-wake schedules and physiologic circadian marker rhythms, may be used to extrapolate phase relationships appropriate- ly from individual and species to species; 3) Endogenous activity of natural immunologic defense networks have rhythmic circadian, fertility cycle and seasonal variation; 4) The hypophyseal-adrenal network is an important circadian coordinator of cellular immune networks; 5) These networks have rhythmic circadian, fertility cycle and seasonal variation in their ability to be stimulated; 6) The circadian timing of TNF reproducibly affects its toxicity and its antitumor efficacy; 7) The circadian timing of IL-2 reproducibly affects its toxicity and its antitumor efficacy.

建议调查昼夜节律阶段依赖性 重组体的毒性、生物活性和抗癌活性 人肿瘤坏死因子 (rhTNF) 和白细胞介素 2 (rhIL-2) 有或没有植入 Meth-A 肉瘤的 Balb/c 小鼠。 我们发现 初步确定肿瘤接种的昼夜时间和季节 影响肿瘤摄取率和自然杀伤细胞活性。 我们还有 发现在生育周期内肿瘤切除的时机会影响 随后转移性肿瘤扩散的频率以及生育能力 周期影响免疫细胞NK活性水平。 因此，效果 研究时的女性生育周期阶段和季节也将是 量化。 大多数（如果不是全部）营养激素的生物效应都依赖于 在某种程度上取决于它们的释放或管理的时间模式 。 生育能力取决于 FSH 和 LH 输送的脉动 垂体到卵巢和睾丸。 皮质醇释放密切相关 基于 ACTH 的高频脉冲和昼夜节律模式 从垂体输送到肾上腺。 IL-1是一种中枢性 定位细胞因子与 TNF 具有协同活性并相互作用 或对其他几种细胞因子和生长因子的刺激作用。 糖皮质激素（具有精确的昼夜节律）调节 IL-1基因转录率、信使RNA稳定性和 由此产生的翻译率和 IL-1 细胞释放率，以及 TNF- 诱导的细胞毒性。 IL-1 反过来调节糖皮质激素受体 结合，减少可用的结合位点并减少类固醇相关 酶诱导。 这些类固醇/细胞因子相互作用表明 细胞因子毒性和抗癌功效的时间生物学研究 可能很重要。 许多细胞毒性外源物质的毒性和治疗性抗癌作用 抗癌药物取决于其昼夜节律时间。 可重现的峰值 通常毒性和抗癌活性存在昼夜差异 范围在 50% 到 250% 之间。 肿瘤坏死因子的初步数据 表明毒性/治疗的昼夜节律阶段依赖性差异 细胞因子的 ic 比率可能要高得多。 拟议研究要解决的具体假设包括：1) 内源性、可重复性、重要且可量化的昼夜节律（ 受生育周期和季节的可重复调节） 描述（小鼠和人类）正常生物学特征； 2）人口同步， 通过参考睡眠-觉醒时间表和生理昼夜节律来衡量 标记节奏，可用于推断适当的相位关系- 从个体到物种； 3) 内源性活性 自然免疫防御网络具有节律性昼夜节律、生育能力 周期和季节变化； 4) 垂体-肾上腺网络是 细胞免疫网络的重要昼夜节律协调员； 5）这些 网络具有有节奏的昼夜节律、生育周期和季节变化 他们受到刺激的能力； 6) TNF 的昼夜节律可重复 影响其毒性和抗肿瘤功效； 7）昼夜节律 IL-2 可重复地影响其毒性和抗肿瘤功效。