Dual role of IL-16 in dysregulated growth of CTCL cells

IL-16 在 CTCL 细胞生长失调中的双重作用

• 批准号: 8271251
• 负责人: William W Cruikshank
• 金额: $ 32.65万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271251
• 关键词: Address; Affect; Antigens; Apoptosis; Binding; Binding Sites; CD7 gene; CREB1 gene; Cell Count; Cell Cycle; Cell Cycle Progression; Cell Line; Cell Nucleus; Cell surface; Cells; Chimeric Proteins; Chromosomes, Human, Pair 15; Code; Cyclin-Dependent Kinase Inhibitor; DNA Sequence; Data; Dipeptidyl-Peptidase IV; Dose; Fluorescent in Situ Hybridization; G0 Phase; Genes; Genetic Transcription; Growth; Growth Factor; Health; Histone Deacetylase; Human; Hypermethylation; IL2RA gene; Interleukin-15; Interleukin-16; Interleukin-17; Interleukin-7; Location; MLLT7 gene; Malignant - descriptor; Maps; Methylation; Molecular Chaperones; Mus; Mutation; Nuclear; Nuclear Translocation; Patients; Phase; Phenotype; Point Mutation; Production; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Regulatory T-Lymphocyte; Reporting; Resistance; Role; Scaffolding Protein; Sezary Syndrome; Signal Transduction; Site; Staging; Stem cells; Surface; System; T-Cell Proliferation; T-Lymphocyte; TNFRSF8 gene; Therapeutic; Tumor Suppressor Proteins; Virus; cancer cell; cell growth; competence factor; extracellular; genetic regulatory protein; novel strategies; prevent; promoter; protein distribution

DESCRIPTION (provided by applicant): The increase in T cell numbers associated with Sezary Syndrome likely occurs as a result of hyperproliferation as well as decreased apoptosis. The mechanisms involved resulting in these effects however are not clearly understood. We have previously reported that IL-16 is a bi-functional protein involved in regulation of T cell growth. The secreted (mature) portion has been classified as a competence factor that regulates T cell growth through extracellular association with CD4, promoting CD25 expression and transition from the G0 phase to G1. The pro-piece (pro-IL-16) has been recently detected in the nucleus of T cells where it affects proliferation through the regulation of Skp-2 transcription. Pro-IL-16 functions as a scaffold protein which interacts with co- factors GABP1 and HDAC-3 to suppress Skp2 transcription, therefore indirectly regulating degradation of one of the major cyclin kinase inhibitors associated with T cell proliferation, p27kip1. Our preliminary data now indicates that in T cells from CTCL patients there is an initial redistribution of intracellular pro-IL-16 characterized by preferential loss in the nucleus. This loss can be attributable to mutations in the PDZ1 domain, correlating to loss of binding by the nuclear chaperone protein HSC70. The loss of nuclear pro-IL-16 also appears to be combined with an observed increase in secretion of mature IL-16 in stages I-III as intracellular stores become depleted. In addition, there is an overall progressive reduction in the production of IL-16 that may be associated with promoter hypermethylation. It is our hypothesis therefore that the onset of CTCL is associated with hypermethylation of the IL-16 promoter resulting in a progressive reduction in protein production. In addition, mutations in PDZ1 of pro-IL-16 results in loss of HSC70 binding, significantly reducing nuclear expression or function, while increasing secretion of mature protein. Secreted IL-16 interacts with surface expressed CD4 to further induce cell cycle progression in the malignant cells. In these studies we propose to investigate the effects of methylation on the IL-16 promoter as well as within the coding region; to delineate the mechanism by which pro-IL-16 is prevented from nuclear translocation and establish cellular effects of Sezary T cells following expression of wild type pro-IL-16; and finally to determine the role of secreted IL-16 on T cell proliferation and potential expansion of T regulatory cells. PUBLIC HEALTH RELEVANCE: We have shown that nuclear pro-IL-16 functions to regulate T cell progression within the cell cycle and that in Sezary T cells pro-IL-16 has lost the ability to translocate into the nucleus rendering the cells hyperproliferative. In these studies we propose to identity the mechanisms involved in regulating nuclear translocation of pro-IL-16; the ability of expressed wild type pro-IL-16 to regulate hyperproliferation in malignant T cells; and to investigate the role of secreted IL-16 to induce loss of tumor suppressor expression with resultant hyperproliferation. Completion of these studies will not only identify a mechanism for dysregulated growth in Sezary T cells but will elucidate a novel approach to potential therapeutics.

描述（由申请人提供）：与Sezary综合征相关的T细胞数量的增加可能是由于增殖性过高以及凋亡减少而发生的。然而，涉及这些影响的机制尚未清楚地理解。我们以前已经报道说，IL-16是参与调节T细胞生长的双功能蛋白。分泌的（成熟）部分已被归类为通过与CD4细胞外关联来调节T细胞生长的能力因子，从而促进CD25表达并从G0相到G1。最近在T细胞的核中检测到了proe件（Pro-IL-16），在T细胞的核中它通过调节SKP-2转录影响增殖。 Pro-IL-16充当脚手架蛋白，与Co-Con-kabP1和HDAC-3相互作用以抑制SKP2转录，因此间接调节与T细胞增殖相关的主要细胞周期蛋白激酶抑制剂之一的降解，P27KIP1。我们的初步数据现在表明，在CTCL患者的T细胞中，细胞内Pro-IL-16的初始重新分布为特征，其特征是细胞核中的优先损失。这种损失可以归因于PDZ1结构域中的突变，与核伴侣蛋白HSC70结合的丧失相关。随着细胞内存储的耗尽，I-III阶段成熟IL-16分泌的分泌量似乎也与观察到的成熟IL-16分泌的增加似乎也相结合。此外，IL-16的产生总体逐渐减少，可能与启动子高甲基化有关。因此，我们的假设是CTCL的发作与IL-16启动子的高甲基化有关，从而导致蛋白质产生的逐渐减少。此外，Pro-IL-16的PDZ1突变导致HSC70结合的丧失，显着降低了核表达或功能，同时增加了成熟蛋白的分泌。分泌的IL-16与表达的CD4相互作用，以进一步诱导恶性细胞中的细胞周期进程。在这些研究中，我们建议研究甲基化对IL-16启动子以及编码区域内的影响。描绘出野生型Pro-IL-16表达后，阻止Pro-IL-16阻止核易位的机制并建立了Sezary T细胞的细胞作用；最后确定分泌的IL-16在T细胞增殖和T调节细胞的潜在扩张中的作用。 公共卫生相关性：我们已经表明，核IL-16的功能可以调节细胞周期内的T细胞进展，并且在Sezary T细胞中，Pro-IL-16失去了将细胞迁移到细胞过度增殖的细胞核中的能力。在这些研究中，我们建议识别调节Pro-IL-16核易位的机制；表达野生型Pro-IL-16调节恶性T细胞中过度增殖的能力；并研究分泌的IL-16在诱导肿瘤抑制者表达丧失的作用，从而导致过度增殖。这些研究的完成不仅将确定SEZARY T细胞中未调节生长失调的机制，而且还将阐明一种新型的潜在疗法方法。

项目成果

Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis preferentially inhibits sphingosine-1-phosphate-induced migration of Th1 cells.

• DOI: 10.4049/jimmunol.1103092
• 发表时间: 2012-12-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Richmond JM;Lee J;Green DS;Kornfeld H;Cruikshank WW
• 通讯作者: Cruikshank WW

CCR4+T cell recruitment to the skin in mycosis fungoides: potential contributions by thymic stromal lymphopoietin and interleukin-16.

蕈样肉芽肿中 CCR4 T 细胞募集到皮肤：胸腺基质淋巴细胞生成素和白细胞介素 16 的潜在贡献。

• DOI: 10.3109/10428194.2014.919634
• 发表时间: 2015
• 期刊: Leukemia & lymphoma
• 影响因子: 2.6
• 作者: Tuzova,Marina;Richmond,Jillian;Wolpowitz,Deon;Curiel-Lewandrowski,Clara;Chaney,Keri;Kupper,Thomas;Cruikshank,William
• 通讯作者: Cruikshank,William