Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation.
Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation.
复制标题
DOI：
10.1016/j.bcp.2021.114844
复制
发表时间：
2022-01
影响因子：
5.8
通讯作者：
Spivak AM
中科院分区：
文献类型：
--
作者：
Larragoite ET;Nell RA;Martins LJ;Barrows LR;Planelles V;Spivak AM
潜伏期翻转剂(LRAs)，如蛋白激酶C(PKC)激动剂，构成了一种暴露和消除HIV-1潜伏库的有前景的策略。蛋白激酶C激动剂激活NF-κB，诱导有害的促炎细胞因子的产生。辅助性药理学药物，如JAK抑制剂ruxolitinib，以前曾与LRAs联合使用，在体外减少有害的促炎细胞因子的分泌，而不抑制HIV-1的重新激活。众所周知，组蛋白去乙酰酶抑制剂(HDACi)在其他疾病的背景下可以抑制促炎细胞因子的分泌，并与LRA协同作用重新激活潜伏的HIV-1。这项研究调查了包括HDACi在内的一组表观遗传修饰物是否可以在潜伏期逆转过程中抑制PKC诱导的促炎细胞因子的分泌。我们筛选了一个表观遗传修饰物库，以寻找减少PKC激动剂吲哚-3，20-二苯甲酸酯诱导的细胞内IL-6产生的化合物。我们进一步测试了最有希望的表观遗传抑制物类，HDACi，它们在体外减少促炎细胞因子和重新激活潜伏的HIV-1的能力。我们确定了九种表观遗传调节剂，它们可以减少PKC诱导的细胞内IL-6。在HIV-1携带者的细胞中，HDAC1-3抑制剂亚异羟肟酸(SBHA)减少了促炎细胞因子肿瘤坏死因子-α、IL-5、IL-2R和IL-17的分泌，但当与吲哚-3，20-二苯甲酸酯联合使用时，并不显著地重新激活潜伏的艾滋病毒-1。SBHA和吲哚-3，20-二苯甲酸酯联合使用可减少潜伏期逆转过程中有害细胞因子的产生，但不会在无性生殖供者PBMC中诱导显著的病毒重新激活。SBHA能够减少PKC诱导的促炎细胞因子，当与吲哚-3，20-二苯甲酸酯结合时，表明SBHA可用于减少PKC诱导的促炎细胞因子，但不能在HIV-1的背景下实现潜伏期逆转。
Latency reversal agents (LRAs), such as protein kinase C (PKC) agonists, constitute a promising strategy for exposing and eliminating the HIV-1 latent reservoir. PKC agonists activate NF-κB and induce deleterious pro-inflammatory cytokine production. Adjuvant pharmacological agents, such as ruxolitinib, a JAK inhibitor, have previously been combined with LRAs to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 reactivation in vitro. Histone deacetylase inhibitors (HDACi) are known to dampen pro-inflammatory cytokine secretion in the context of other diseases and synergize with LRAs to reactivate latent HIV-1. This study investigates whether a panel of epigenetic modifiers, including HDACi, could dampen PKC-induced pro-inflammatory cytokine secretion during latency reversal. We screened an epigenetic modifier library for compounds that reduced intracellular IL-6 production induced by the PKC agonist Ingenol-3,20-dibenzoate. We further tested the most promising epigenetic inhibitor class, HDACi, for their ability to reduce pro-inflammatory cytokines and reactivate latent HIV-1 ex vivo. We identified nine epigenetic modulators that reduced PKC-induced intracellular IL-6. In cells from aviremic individuals living with HIV-1, the HDAC1–3 inhibitor, suberohydroxamic acid (SBHA), reduced secretion of pro-inflammatory cytokines TNF-α, IL-5, IL-2r, and IL-17 but did not significantly reactivate latent HIV-1 when combined with Ingenol-3,20-dibenzoate. Combining SBHA and Ingenol-3,20-dibenzoate reduces deleterious cytokine production during latency reversal but does not induce significant viral reactivation in aviremic donor PBMCs. The ability of SBHA to reduce PKC-induced pro-inflammatory cytokines when combined with Ingenol-3,20-dibenzoate suggests SBHA can be used to reduced PKC induced pro-inflammatory cytokines but not to achieve latency reversal in the context of HIV-1.
登录
查看更多内容
影响因子：
158.5
作者：
Gulick, RM;Mellors, JW;Chodakewitz, JA
通讯作者：
Chodakewitz, JA
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
4.1
作者：
Borges AH;Dubrow R;Silverberg MJ
通讯作者：
Silverberg MJ
影响因子：
5.6
作者：
Divsalar, Donya Naz;Simoben, Conrad Veranso;Tietjen, Ian
通讯作者：
Tietjen, Ian
使用细胞因子的组合在潜在感染的CD4+ T细胞中诱导HIV-1复制。
DOI：
10.1084/jem.188.1.83
发表时间：
1998-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--