Mycobacterium tuberculosis impairs protective cytokine production via transcription factor MafB manipulation

Although an increased expression of the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) has been reported in patients with active tuberculosis (TB), its potential role in Mycobacterium tuberculosis infection remains unknown. Herein, we report that MafB in macrophages is a regulator of the pro-inflammatory cytokines, TNF-α and IL-12p40, which are crucial for host defense against M. tuberculosis infection. Cell-based luciferase assays showed that MafB inhibited TNF-α and IL-12p40 transcriptional activity in a dose-dependent manner. At the molecular level, MafB interacted with IFN regulatory factor (IRF)-5 and PU.1 and inhibited IRF-5- and PU.1-mediated transactivation, via the basic-leucine zipper domain. Analysis using gene-deficient macrophages demonstrated that the suppressed pro-inflammatory cytokine production during M. tuberculosis infection depends on MafB expression. Finally, in vivo studies indicated that M. tuberculosis-mediated increase of MafB expression was responsible for the exacerbation of M. tuberculosis infection. Thus, our results provide a functional view of MafB as a cytokine regulator as well as novel insights into host factors involved in TB susceptibility.