PMID- 29991810
OWN - NLM
STAT- MEDLINE
DCOM- 20191125
LR  - 20230926
IS  - 2041-4889 (Electronic)
VI  - 9
IP  - 7
DP  - 2018 Jul 10
TI  - Regulation and biological role of the peptide/histidine transporter SLC15A3 in 
      Toll-like receptor-mediated inflammatory responses in macrophage.
PG  - 770
LID - 10.1038/s41419-018-0809-1 [doi]
LID - 770
AB  - The peptide/histidine transporter SLC15A3 is responsible for transporting 
      histidine, certain dipeptide and peptidomimetics from inside the lysosome to 
      cytosol. Previous studies have indicated that SLC15A3 transcripts are mainly 
      expressed in the lymphatic system, however, its regulation and biological role in 
      innate immune responses and inflammatory diseases are as yet unknown. In this 
      study, mouse peritoneal macrophages (PMs), mouse bone marrow-derived macrophages 
      (BMDMs), the human acute monocytic leukemia cell line THP-1 and the human lung 
      epithelial carcinoma cell line A549 were used to investigate the regulation and 
      biological role of SLC15A3 in TLR-mediated inflammatory responses. Our results 
      showed that SLC15A3 was upregulated by TLR2, TLR4, TLR7 and TLR9 ligands in 
      macrophages at both the mRNA and protein levels via activation of NF-kappaB (nuclear 
      factor-kappa-B), MAPK (mitogen-activated protein kinase) and IRF3 (interferon 
      regulatory factor 3). Furthermore, knockdown or overexpression of SLC15A3 
      influenced the TLR4-triggered expression of proinflammatory cytokines. A reporter 
      gene assay showed that the SLC15A3 promotor contained potential NF-kappaB binding 
      sites, which were reasonable for regulating SLC15A3 by TLR-activation through 
      NF-kappaB signaling. Additionally, SLC15A3 expression was increased and positively 
      related to inflammation in mice with bacterial peritonitis. The collective 
      findings suggest that SLC15A3 is regulated by various TLRs, and that it plays an 
      important role in regulating TLR4-mediated inflammatory responses.
FAU - Song, Feifeng
AU  - Song F
AD  - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key 
      Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou, 310058, Zhejiang, China.
FAU - Yi, Yaodong
AU  - Yi Y
AD  - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key 
      Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou, 310058, Zhejiang, China.
FAU - Li, Cui
AU  - Li C
AD  - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key 
      Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou, 310058, Zhejiang, China.
FAU - Hu, Yongjun
AU  - Hu Y
AUID- ORCID: 0000-0002-1883-0868
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Michigan, Ann Arbor, Michigan, 48109, United States.
FAU - Wang, Jinhai
AU  - Wang J
AD  - The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 
      Qingchun Road, Hangzhou, 310003, Zhejiang, China.
FAU - Smith, David E
AU  - Smith DE
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, University of 
      Michigan, Ann Arbor, Michigan, 48109, United States.
FAU - Jiang, Huidi
AU  - Jiang H
AD  - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key 
      Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, 
      Zhejiang University, Hangzhou, 310058, Zhejiang, China. hdjiang@zju.edu.cn.
LA  - eng
GR  - R01 GM115481/GM/NIGMS NIH HHS/United States
GR  - 81573492/National Natural Science Foundation of China (National Science 
      Foundation of China)/International
GR  - R01GM115481/Foundation for the National Institutes of Health (Foundation for the 
      National Institutes of Health, Inc.)/International
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180710
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Interferon Regulatory Factor-3)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Pathogen-Associated Molecular Pattern Molecules)
RN  - 0 (SLC15A3 protein, human)
RN  - 0 (SLC15A3 protein, mouse)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptor 7)
RN  - 0 (Toll-Like Receptor 9)
RN  - 0 (Toll-Like Receptors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - A549 Cells
MH  - Animals
MH  - Cell Line
MH  - Cells, Cultured
MH  - Humans
MH  - Interferon Regulatory Factor-3/metabolism
MH  - Macrophages/drug effects/*metabolism
MH  - Male
MH  - Membrane Transport Proteins/genetics/*metabolism
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Pathogen-Associated Molecular Pattern Molecules/pharmacology
MH  - Peritonitis/metabolism/microbiology
MH  - THP-1 Cells
MH  - Toll-Like Receptor 2/agonists/metabolism
MH  - Toll-Like Receptor 4/agonists/metabolism
MH  - Toll-Like Receptor 7/agonists/metabolism
MH  - Toll-Like Receptor 9/agonists/metabolism
MH  - Toll-Like Receptors/*metabolism
PMC - PMC6039463
COIS- The authors declare that they have no conflict of interest.
EDAT- 2018/07/12 06:00
MHDA- 2019/11/26 06:00
PMCR- 2018/07/10
CRDT- 2018/07/12 06:00
PHST- 2018/02/28 00:00 [received]
PHST- 2018/06/15 00:00 [accepted]
PHST- 2018/05/08 00:00 [revised]
PHST- 2018/07/12 06:00 [entrez]
PHST- 2018/07/12 06:00 [pubmed]
PHST- 2019/11/26 06:00 [medline]
PHST- 2018/07/10 00:00 [pmc-release]
AID - 10.1038/s41419-018-0809-1 [pii]
AID - 809 [pii]
AID - 10.1038/s41419-018-0809-1 [doi]
PST - epublish
SO  - Cell Death Dis. 2018 Jul 10;9(7):770. doi: 10.1038/s41419-018-0809-1.