CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS

艾滋病合并症中细胞因子和激素的相互作用

• 批准号: 6930551
• 负责人: Keith W Kelley
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6930551
• 关键词: AIDS; anemia; cachexia; cell line; ceramides; comorbidity; cytokine; growth factor receptors; hormone receptor; hormone regulation /control mechanism; insulin receptor; insulinlike growth factor; interleukin 1; molecular pathology; myeloid stem cell; myoblasts; myotubes; neutropenia; phosphatidylinositol 3 kinase; protein biosynthesis; protein kinase; sarcopenia; serine proteinases; transcription factor; tyrosine

DESCRIPTION (provided by applicant): The anemia, neutropenia, loss of lean body mass and mortality of AIDS patients with wasting are associated with elevated levels of the proinflammatory cytokines TNFalpha and IL-1beta. AIDS patients with wasting are often given a 12- week therapy with very high doses of recombinant human growth hormone to increase plasma IGF-I, lean muscle mass and quality of life. However, the responsiveness of both hematopoietic and muscle cells to IGF-I has been documented to be defective in these patients. The central hypothesis of this application is that TNFalpha and IL-lbeta are responsible for inducing a state of IGF-I receptor resistance, which contributes to not only muscle wasting but also to the anemia and neutropenia of AIDS. IGF-I targets both hematopoietic myeloid progenitor cells and muscle myoblasts, and here we hypothesize that the molecular mechanism for IGF-I receptor resistance in wasting AIDS patients is caused by proinflammatory cytokines. Objective 1 will test the idea that IGF-I promotes promyeloid cell survival by blocking activation of the caspase family of serine proteases and whether this is inhibited by TNFa. Objective 2 focuses on the survival promoting activity of the tyrosine phosphorylated IGF-I receptor, including insulin-receptor substrate- 1 (IRS-1), IRS-2, PI 3-kinase and Akt. Objective 3 will determine if proinflammatory cytokines inhibit key IGF-I proliferative signals, including Shc, EFK1/2, AFX forkhead transcription factors and the cyclin-dependent kinase inhibitor 27. Finally, objective 4 will extend these results with myeloid progenitor cells to muscle myoblasts. Preliminary results indicate that low blood concentrations of TNFalpha and IL-1beta found in wasting AIDS patients inhibit the ability of IGF-I to promote both protein synthesis and differentiation into myotubes. This objective will also test the new idea that ceramide, a mediator of the actions of both TNFalpha and IL-1beta, induces resistance of the IGF-I receptor in muscle myoblasts. These studies are needed to understand how clinically-relevant concentrations of proinflammatory cytokines in wasting AIDS patients impair the functional ability of a major hormone receptor on both immune and muscle myoblast cells.

描述（由申请人提供）：贫血、中性粒细胞减少、瘦身损失 患有消瘦的艾滋病患者的质量和死亡率与升高有关 促炎细胞因子 TNFα 和 IL-1β 的水平。艾滋病患者患有 消瘦患者通常会接受为期 12 周的高剂量重组治疗 人类生长激素可增加血浆 IGF-I、瘦肌肉质量和肌肉质量 生活。然而，造血细胞和肌肉细胞对 IGF-I 已被证明在这些患者中存在缺陷。中央 本申请的假设是 TNFα 和 IL-1β 负责 诱导 IGF-I 受体抵抗状态，这不仅有助于 肌肉萎缩还会导致艾滋病引起的贫血和中性粒细胞减少症。 IGF-I 靶点 造血骨髓祖细胞和肌肉成肌细胞，在这里我们 假设 IGF-I 受体抵抗的分子机制 艾滋病患者的消瘦是由促炎细胞因子引起的。目标 1 将 检验 IGF-I 通过阻断促进早幼粒细胞存活的观点 丝氨酸蛋白酶半胱天冬酶家族的激活以及这是否是 受TNFα抑制。目标 2 侧重于促进生存的活动 酪氨酸磷酸化 IGF-I 受体，包括胰岛素受体 底物- 1 (IRS-1)、IRS-2、PI 3-激酶和 Akt。目标 3 将确定是否 促炎细胞因子抑制关键的 IGF-I 增殖信号，包括 Shc、EFK1/2、AFX 叉头转录因子和细胞周期蛋白依赖性激酶 抑制剂 27。最后，目标 4 将用骨髓细胞扩展这些结果 祖细胞为肌肉成肌细胞。初步结果表明，低 在消瘦的艾滋病患者中发现的 TNFα 和 IL-1β 血液浓度抑制 IGF-I 促进蛋白质合成和分化的能力 肌管。该目标还将测试神经酰胺（一种介质）的新想法 TNFα 和 IL-1β 的作用，诱导 IGF-I 受体抵抗 在肌肉成肌细胞中。需要这些研究来了解如何 消瘦型艾滋病患者促炎细胞因子的临床相关浓度 患者的主要激素受体功能受损 免疫和肌肉成肌细胞。

项目成果

Exaggerated expression of skeletal muscle-derived interleukin-6, but not TNFalpha, in mice lacking interleukin-10.

在缺乏白细胞介素 10 的小鼠中，骨骼肌来源的白细胞介素 6 过度表达，但 TNFα 不表达。

• DOI: 10.1016/j.jneuroim.2008.05.004
• 发表时间: 2008
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Huey,KimberlyA;McCusker,RobertH;Kelley,KeithW
• 通讯作者: Kelley,KeithW

Tumor necrosis factor alpha inhibits cyclin A expression and retinoblastoma hyperphosphorylation triggered by insulin-like growth factor-I induction of new E2F-1 synthesis.

肿瘤坏死因子 α 抑制细胞周期蛋白 A 表达和由胰岛素样生长因子-I 诱导新 E2F-1 合成引发的视网膜母细胞瘤过度磷酸化。

• DOI: 10.1074/jbc.m310264200
• 发表时间: 2004
• 期刊: The Journal of biological chemistry
• 作者: Shen,WenHong;Yin,Yuxin;Broussard,SuzanneR;McCusker,RobertH;Freund,GregoryG;Dantzer,Robert;Kelley,KeithW
• 通讯作者: Kelley,KeithW