de Oliveira Rezende Aline, Sabóia Rafaella Santos, da Costa Adeliane Castro, da Silva Monteiro Diana Messala Pinheiro, Zagmignan Adrielle, Santiago Luis Ângelo Macedo, Carvalho Rafael Cardoso, Pereira Paulo Vitor Soeiro, Junqueira-Kipnis Ana Paula, de Sousa Eduardo Martins
Graduate Program in Health Sciences, Federal University of Maranhão-UFMA, São Luís 65080-805, Brazil.
Graduate Program in Microbial Biology, CEUMA University-UniCEUMA, São Luís 65075-120, Brazil.
Biomedicines. 2022 Mar 31;10(4):817. doi: 10.3390/biomedicines10040817.
Tuberculous granuloma formation is mediated by hypoxia-inducible factor 1 alpha (HIF-1α), and is essential for establishing latent tuberculosis infection (LTBI) and its progression to active tuberculosis (TB). Here, we investigated whether HIF-1α expression and adjacent mechanisms were associated with latent or active TB infection. Patients with active TB, individuals with LTBI, and healthy controls were recruited, and the expression of cytokine genes , , , , , and in peripheral blood mononuclear cells (PBMCs) and serum vitamin D (25(OH)D3) levels were evaluated. Additionally, nuclear factor kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α) levels were analyzed in PBMC lysates and culture supernatants, respectively, after HIF-1α blockade with 2-methoxyestradiol. We observed that IL-15 expression was higher in individuals with LTBI than in patients with active TB, while IL-18 and TNF-α expression was similar between LTBI and TB groups. Additionally, serum 25(OH)D3 levels and expression of , , and were higher in patients with active TB than in individuals with LTBI. Moreover, PBMCs from individuals with LTBI showed decreased NF-κB phosphorylation and increased TNF-α production after HIF-1α blockade. Together, these results suggest that under hypoxic conditions, TNF-α production and NF-κB pathway downregulation are associated with the LTBI phenotype.
结核性肉芽肿的形成由缺氧诱导因子1α（HIF-1α）介导，对于建立潜伏性结核感染（LTBI）及其进展为活动性结核病（TB）至关重要。在此，我们研究了HIF-1α的表达及相关机制是否与潜伏性或活动性结核感染相关。招募了活动性结核患者、LTBI个体和健康对照，评估外周血单核细胞（PBMCs）中细胞因子基因、、、、、和的表达以及血清维生素D（25(OH)D3）水平。此外，在用2-甲氧基雌二醇阻断HIF-1α后，分别分析PBMC裂解物和培养上清液中的核因子κB（NF-κB）和肿瘤坏死因子-α（TNF-α）水平。我们观察到，LTBI个体中IL-15的表达高于活动性结核患者，而LTBI组和TB组之间IL-18和TNF-α的表达相似。此外，活动性结核患者血清25(OH)D3水平以及、、和的表达高于LTBI个体。而且，LTBI个体的PBMCs在HIF-1α阻断后显示NF-κB磷酸化降低且TNF-α产生增加。总之，这些结果表明在缺氧条件下，TNF-α的产生和NF-κB途径下调与LTBI表型相关。
