Tuberculosis antigen-induced expression of IFN-α in tuberculosis patients inhibits production of IL-1β

The mechanism by which IFN-alpha regulates the host response to Mycobacterium tuberculosis (M. tb) infection in humans is poorly understood. In the present study, we found that freshly isolated pleural fluid mononuclear cells (PFMCs) from tuberculous pleural effusion but not peripheral blood mononuclear cells (PBMCs) spontaneously expressed IFN-alpha and IL-1 beta in vivo. In addition, exogenous IFN-alpha significantly inhibited production of IL-1 beta in PFMCs after stimulation with Bacillus Calmette-Guerin (BCG). To further evaluate the effect of endogenous IFN-alpha on BCG-induced IL-1 beta production, a neutralizing antibody to IFN-alpha was added to the cultures of BCG-stimulated PFMCs. As expected, neutralization of IFN-alpha by antibody significantly enhanced the production of IL-1 beta. Notably, we showed that IFN-alpha inhibited production of IL-1 beta through 2 distinct mechanisms: IFN-alpha signaling, via the STAT1 transcription factor, suppressed caspase-1-dependent IL-1 beta maturation, and IFN-alpha induced the production of IL-10 in a STAT1-dependent manner in which IL-10 reduced the abundance of IL-1 beta. In contrast, we found that IFN-alpha enhanced the production of IFN-gamma, and IFN-gamma also suppressed IL-1 beta production in the PFMCs during BCG stimulation. Our findings demonstrate that IFN-alpha employs distinct pathways for regulating IL-1 beta production and reveal that in the case of M. tb infection, the induction of IFN-alpha and IFN-gamma might be associated with M. tb immune escape and disease progression in infected humans.