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Jang, Ah-Ra,Choi, Joo-Hee,Shin, Sung Jae,Park, Jong-Hwan Elsevier 2018 Cytokine Vol.104 No.-
<P><B>Abstract</B></P> <P> <I>Mycobacterium tuberculosis</I> is a highly virulent bacterium that causes tuberculosis. It infects about one third of the world’s population. Type I interferons (IFNs) play a detrimental role in host defense against <I>M. tuberculosis</I> infection. Proteins secreted by <I>M. tuberculosis</I> through ESX-1 secretion system contribute to type I IFNs production. However, the precise mechanism by which 6-kDa early secretory antigen target (ESAT6), one of ESX-1-mediated secretory proteins, induces type I IFNs production in host cells is currently unclear. Therefore, the objective of the present study was to determine the underlying molecular mechanism regulating ESAT6-mediated gene expression of IFN-β in macrophages. Recombinant ESAT6 produced from <I>E. coli</I> expression system induced IFN-β gene expression in various types of macrophages such as mouse bone marrow-derived macrophages (BMDMs), peritoneal macrophages, and MH-S cells (murine alveolar macrophage cell line). Deficiency of TLR4 and TRIF absolutely abrogated ESAT6-induced IFN-β gene expression. TLR2 and MyD88 were partially involved in IFN-β gene expression in response to low dose of ESAT6. Another recombinant ESAT6 produced from baculovirus system also upregulated IFN-β gene expression via TLR4-dependent pathway. Polymyxin B (PMB) treatment impaired LPS-induced IFN-β expression. However, IFN-β expression induced by ESAT6 was not influenced by PMB. This suggests that ESAT6-mediated IFN-β expression is not due to LPS contamination. Treatment with ESAT6 resulted in activation of TBK1 and IRF3 in macrophages. Such activation was abolished in TLR4- and TRIF-deficient cells. Moreover, inhibition of IRF3 and TBK1 suppressed IFN-β gene expression in response to ESAT6. Our results suggest that ESAT6 might contribute to virulence of <I>M. tuberculosis</I> by regulating type I IFNs production through TLR4-TRIF signaling pathway.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TLR4-TRIF signaling is essential for <I>M. tuberculosis</I> ESAT6-induced IFN-β expression. </LI> <LI> TLR2 and MyD88 are partially involved in IFN-β expression by low dose of ESAT6. </LI> <LI> ESAT6 activates TBK1 and IRF3 in macrophages through TLR4-TRIF pathway. </LI> <LI> Both TBK1 and IRF3 are required for ESAT6-induced IFN-β expression. </LI> </UL> </P>