Nieto-Patlán Erik, Serafín-López Jeanet, Wong-Baeza Isabel, Pérez-Tapia Sonia M, Cobos-Marín Laura, Estrada-Parra Sergio, Estrada-García Iris, Chávez-Blanco Alma D, Chacón-Salinas Rommel
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), ENCB-IPN, Mexico; Laboratorio de Virología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México (UNAM), Mexico.
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional (IPN), ENCB-IPN, Mexico.
Tuberculosis (Edinb). 2019 Jan;114:123-126. doi: 10.1016/j.tube.2018.12.007. Epub 2019 Jan 2.
Tuberculosis is one of the leading causes of mortality worldwide, it is caused by Mycobacterium tuberculosis (Mtb), a bacteria that employs several strategies to evade the host immune response. For instance, Mtb interferes with the overexpression of class II transactivator (CIITA) in macrophages exposed to IFN-γ by inhibiting histone acetylation at its promoter, which can be reverted by the histone deacetylase inhibitor (HDACi) sodium butyrate. In this work, we evaluated whether a different HDACi, valproic acid (VPA), could revert the inhibition of gene expression induced by Mtb. J774 macrophages treated with VPA and IFN-γ unexpectedly induced a higher expression of the inducible nitric oxide synthase and a higher production of nitric oxide when exposed to the 19 kDa lipoprotein of Mtb or the whole bacteria. However, VPA was unable to revert the inhibition of CIITA expression induced by the 19 kDa lipoprotein of Mtb. Finally, macrophages infected with Mtb and treated with VPA and IFN-γ showed a significant reduction in intracellular bacteria. Our findings suggest a new therapeutic potential of VPA for the treatment of tuberculosis.
结核病是全球主要死因之一，它由结核分枝杆菌（Mtb）引起，该细菌采用多种策略逃避宿主免疫反应。例如，Mtb通过抑制巨噬细胞中II类反式激活因子（CIITA）启动子处的组蛋白乙酰化来干扰其在暴露于IFN-γ时的过表达，而组蛋白脱乙酰酶抑制剂（HDACi）丁酸钠可逆转这种抑制。在这项研究中，我们评估了另一种HDACi丙戊酸（VPA）是否能逆转Mtb诱导的基因表达抑制。用VPA和IFN-γ处理的J774巨噬细胞在暴露于Mtb的19 kDa脂蛋白或整个细菌时，意外地诱导了诱导型一氧化氮合酶的更高表达和一氧化氮的更高产生。然而，VPA无法逆转Mtb的19 kDa脂蛋白诱导的CIITA表达抑制。最后，感染Mtb并用VPA和IFN-γ处理的巨噬细胞显示细胞内细菌显著减少。我们的研究结果表明VPA在治疗结核病方面具有新的治疗潜力。
