Restricted Activation of the NF-κB Pathway in Individuals with Latent Tuberculosis Infection after HIF-1α Blockade

Tuberculous granuloma formation is mediated by hypoxia-inducible factor 1 alpha (HIF-1 alpha), and is essential for establishing latent tuberculosis infection (LTBI) and its progression to active tuberculosis (TB). Here, we investigated whether HIF-1 alpha 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 IL15, IL18, TNFA, IL6, HIF1A, and A20 in peripheral blood mononuclear cells (PBMCs) and serum vitamin D (25(OH)D3) levels were evaluated. Additionally, nuclear factor kappa B (NF-kappa B) and tumor necrosis factor-alpha (TNF-alpha) levels were analyzed in PBMC lysates and culture supernatants, respectively, after HIF-1 alpha 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-alpha expression was similar between LTBI and TB groups. Additionally, serum 25(OH)D3 levels and expression of IL-6, HIF1A, and A20 were higher in patients with active TB than in individuals with LTBI. Moreover, PBMCs from individuals with LTBI showed decreased NF-kappa B phosphorylation and increased TNF-alpha production after HIF-1 alpha blockade. Together, these results suggest that under hypoxic conditions, TNF-alpha production and NF-kappa B pathway downregulation are associated with the LTBI phenotype.