Activation of IL1 signaling molecules by Kaposi's sarcoma-associated herpesvirus.
Activation of IL1 signaling molecules by Kaposi's sarcoma-associated herpesvirus.
复制标题
DOI：
10.3389/fcimb.2022.1049624
复制
发表时间：
2022
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
--
作者：
卡波西肉瘤相关疱疹病毒 (KSHV) 是多种人类癌症的病原体，包括卡波西肉瘤 (KS) 和原发性渗出性淋巴瘤 (PEL)，这些癌症通常见于免疫功能低下的患者，但缺乏有效的治疗选择。白细胞介素1 (IL1) 家族是炎症反应的主要介质，在先天免疫和适应性免疫中发挥功能作用。与充分研究的 IL1 分子相比，IL1 受体/辅助受体和其他相关配体（例如 IL1 受体辅助蛋白 (IL1RAP)）在 KSHV 发病机制和肿瘤发生中的激活和功能作用仍然几乎未知。在本研究中，使用一系列KSHV阴性和阳性原代细胞或肿瘤细胞，以及来自HIV+患者队列的AIDS-KS肿瘤样本来比较和确定IL1信号分子的激活状态及其在KSHV发病机制中的功能作用。我们报告了在 KSHV 潜伏期和溶解期以及 KSHV 相关恶性肿瘤患者的临床样本中多种 IL1 信号分子的高度激活，包括 IL1、IL36、IL1R1、IL1RAP 和 IRAK。直接靶向这些分子，尤其是 IL1R1 和 IL1RAP 显着损害了 KSHV+ 肿瘤细胞的存活和生长，以及它们在 3-D 培养中的集落形成。我们的数据表明 IL1 信号分子在 KSHV 发病机制和肿瘤发生中的重要性，这可能代表针对这些病毒相关疾病的有吸引力的治疗靶点。
Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and Primary effusion lymphoma (PEL), which are usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin1 (IL1) family is a major mediator for inflammation response and has functional role in both innate and adaptive immunity. In contrast to the well-studied IL1 molecules, the activation and functional role of IL1 receptor/co-receptor and other related ligands, such as the IL1 receptor accessory protein (IL1RAP), in KSHV pathogenesis and tumorigenesis remain almost unknown. In the current study, a series of KSHV negative and positive primary or tumor cells, as well as AIDS-KS tumor samples from cohort HIV+ patients were used to compare and determine the activation status of IL1 signaling molecules, and their functional roles in KSHV pathogenesis. We reported the high activation of multiple IL1 signaling molecules, including IL1, IL36, IL1R1, IL1RAP and IRAKs, during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV-related malignancies. Directly targeting these molecules especially IL1R1 and IL1RAP significantly impaired the survival and growth of KSHV+ tumor cells, as well as their colony formation on 3-D culture. Our data indicate the importance of IL1 signaling molecules in KSHV pathogenesis and tumorigenesis, which may represent attractive therapeutic targets against these virus-associated diseases.