ArticleFrontiers in immunology2026
Forkhead box O3 transcription factor fine-tunes IL-6 expression in mycobacteria-infected macrophages.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: Tuberculosis (TB) remains the deadliest infectious disease in humans; however, a robust immune response can either protect against or control the infection. Household contacts of TB patients can remain uninfected for decades, while a quarter of the world's population that is latently infected can remain healthy for years. Characterization of the effectors of such an immune response would help in developing novel host-directed tools to better treat and/or prevent TB. IL-6 is a crucial cytokine that plays a central role in orchestrating a protective TB immune response; however, a delicate balance between its beneficial and detrimental effects must be maintained to effectively control the infection. Here, we aimed to characterize the cellular effectors that regulate IL-6 expression in mycobacteria-infected cells. Methods: We used PI3K and AKT inhibitors, as well as FOXO3-specific siRNA, to modulate FOXO3 activity in BCG-infected macrophages and assessed the effect on IL-6 expression. Reporter gene assays were performed using four IL-6 promoter constructs (-600 bp, -900 bp, -1.5 kb, and -2 kb). Results: The PI3K/AKT/FOXO3 axis regulates IL-6 expression in human macrophages: FOXO3 activation (via PI3K or AKT inhibition) induced IL-6 expression, while FOXO3 silencing reduced IL-6 production in BCG-infected macrophages. FOXO3 positively regulated IL-6 promoter activity across all cloned fragments, with the strongest effect at -1.5 kb; extension to -2 kb modulated this FOXO3-mediated induction. Discussion: We report for the first time that FOXO3 exerts both positive and negative regulation of IL-6 transcription, fine-tuning its expression in mycobacteria-infected macrophages. Together with our previous report on FOXO3-mediated suppression of IL-10, these results highlight the crucial role of FOXO3 in the TB immune response and support targeting the PI3K/Akt/FOXO3 axis as a host-directed approach to improve TB treatment and prevention.
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