PMID- 29046251
OWN - NLM
STAT- MEDLINE
DCOM- 20190429
LR  - 20211204
IS  - 1096-0023 (Electronic)
IS  - 1043-4666 (Linking)
VI  - 104
DP  - 2018 Apr
TI  - Mycobacterium tuberculosis ESAT6 induces IFN-beta gene expression in Macrophages via 
      TLRs-mediated signaling.
PG  - 104-109
LID - S1043-4666(17)30297-1 [pii]
LID - 10.1016/j.cyto.2017.10.006 [doi]
AB  - Mycobacterium tuberculosis 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 M. 
      tuberculosis infection. Proteins secreted by M. tuberculosis 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-beta in macrophages. Recombinant ESAT6 produced from E. coli 
      expression system induced IFN-beta 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-beta gene expression. TLR2 and MyD88 
      were partially involved in IFN-beta gene expression in response to low dose of 
      ESAT6. Another recombinant ESAT6 produced from baculovirus system also 
      upregulated IFN-beta gene expression via TLR4-dependent pathway. Polymyxin B (PMB) 
      treatment impaired LPS-induced IFN-beta expression. However, IFN-beta expression 
      induced by ESAT6 was not influenced by PMB. This suggests that ESAT6-mediated 
      IFN-beta 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-beta gene expression in response to ESAT6. Our results suggest that ESAT6 might 
      contribute to virulence of M. tuberculosis by regulating type I IFNs production 
      through TLR4-TRIF signaling pathway.
CI  - Copyright (c) 2017 Elsevier Ltd. All rights reserved.
FAU - Jang, Ah-Ra
AU  - Jang AR
AD  - Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National 
      University, Gwangju 61186, Republic of Korea.
FAU - Choi, Joo-Hee
AU  - Choi JH
AD  - Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National 
      University, Gwangju 61186, Republic of Korea.
FAU - Shin, Sung Jae
AU  - Shin SJ
AD  - Department of Microbiology, Institute for Immunology and Immunological Diseases, 
      Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of 
      Medicine, Seoul 03722, Republic of Korea.
FAU - Park, Jong-Hwan
AU  - Park JH
AD  - Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National 
      University, Gwangju 61186, Republic of Korea. Electronic address: 
      jonpark@jnu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171016
PL  - England
TA  - Cytokine
JT  - Cytokine
JID - 9005353
RN  - 0 (Antigens, Bacterial)
RN  - 0 (Bacterial Proteins)
RN  - 0 (ESAT-6 protein, Mycobacterium tuberculosis)
RN  - 0 (Interferon Regulatory Factor-3)
RN  - 0 (Irf3 protein, mouse)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Toll-Like Receptors)
RN  - 77238-31-4 (Interferon-beta)
RN  - EC 2.7.1.- (Tbk1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antigens, Bacterial/*metabolism
MH  - Bacterial Proteins/*metabolism
MH  - Bone Marrow Cells/drug effects/metabolism
MH  - Cell Line
MH  - *Gene Expression Regulation/drug effects
MH  - Interferon Regulatory Factor-3/metabolism
MH  - Interferon-beta/*genetics/metabolism
MH  - Kinetics
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages/drug effects/*metabolism
MH  - Mice, Inbred C57BL
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - *Signal Transduction/drug effects
MH  - Toll-Like Receptors/*metabolism
OTO - NOTNLM
OT  - ESAT6
OT  - IFN-beta
OT  - Macrophages
OT  - Mycobacterium tuberculosis
OT  - TLRs
EDAT- 2017/10/20 06:00
MHDA- 2019/04/30 06:00
CRDT- 2017/10/20 06:00
PHST- 2017/06/14 00:00 [received]
PHST- 2017/09/29 00:00 [revised]
PHST- 2017/10/02 00:00 [accepted]
PHST- 2017/10/20 06:00 [pubmed]
PHST- 2019/04/30 06:00 [medline]
PHST- 2017/10/20 06:00 [entrez]
AID - S1043-4666(17)30297-1 [pii]
AID - 10.1016/j.cyto.2017.10.006 [doi]
PST - ppublish
SO  - Cytokine. 2018 Apr;104:104-109. doi: 10.1016/j.cyto.2017.10.006. Epub 2017 Oct 
      16.