Virulent Mycobacteria Upregulate Interleukin-6 (IL6) Production to Combat Innate Immunity

Abstract Tuberculosis is still a major threat to the human population, and understanding the strategies employed by Mycobacterium tuberculosis has been a challenge to researchers for decades. The significance of IL6 production in tuberculosis is still not clear, although it has been known for quite some time that IL6 interferes with IFN-γ induced signaling. Recently, research from our laboratory has identified a significant strategy adopted by virulent mycobacteria. Virulent mycobacteria upregulate IL6 production to inhibit IFN-γ induced autophagy formation, and thus avoid phagosome maturation and subsequent killing by lysosomal enzymes. This report is based on several observations. Exogenous IL6 inhibits IFN-γ induced autophagy in M . tuberculosis H37Rv-infected macrophages. M . tuberculosis H37Rv infection results in time-dependent production of IL6 in THP-1 cells, and neutralization of this endogenous IL6 by anti-IL6 antibody significantly enhances IFN-γ mediated killing of the intracellular bacteria. IL6 time-dependently lowers the Atg12–Atg5 complex and therefore inhibits autophagosome biogenesis rather than autophagolysosome formation. IL6 also affects IFN-γ mediated stimulation of mTOR, p38, and JNK pathways.