2010 Fiscal Year Final Research Report
Analyzing the biological significance in intracellular localization of Toll Like Receptors
Project/Area Number |
21890050
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Single-year Grants |
Research Field |
Immunology
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Research Institution | The University of Tokyo |
Principal Investigator |
SHIBATA Takuma The University of Tokyo, 医科学研究所, 特任研究員 (30554505)
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Project Period (FY) |
2009 – 2010
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Keywords | TLR4 / LPS / TLR5 / Flagellin / PRAT4A / マクロファージ / 細胞内分布 |
Research Abstract |
Toll-like receptor s(TLRs) sense a variety of microbial products. TLRs activate innate immune responses and prime adaptive immune responses. TLR4/MD-2, a sensor for LPS, delivers the MyD88-dependent signal from the cellsurface, then traffics to endolysosomes and delivers the TRIF/TICAM-1-dependent signal. Both signals are thought to be dependent on cell surface TLR4/MD-2. Although TLR4/MD-2 is located also in recycling endosomes, the Golgi apparatus or the endoplasmic reticulum, little is known abouta role for intracellular TLR4/MD-2 in LPS responses. We here studied intracellular LPS sensing in macrophages. PRAT4A (protein associated with TLR4 A) is a cochaperone for a general chaperone gp96 and required for cell surface expression of TLR4/MD-2. Cell surface TLR4/MD-2 was undetectable on PRAT4A deficient thioglycollate-elicited peritoneal macrophage cells (P-Macs) and bone marrow-derived macrophages (BM-Macs). LPS responses were all abolished in PRAT4A deficient P-Macs, whereas a part of LPS responses remained detectable in PRAT4A deficient BM-Macs. Of note, LPS responses in PRAT4A deficient BM-Macs were not necessarily dependent on TRIF/TICAM-1 signaling. PRAT4A deficient BM-Macs showed unimpaired production of both TRIF/TICAM-1-dependent chemokine RANTES (CCL5) and MyD88-dependent chemokine MCP-1 (CCL2). Moreover, up-regulation of co-stimulatory molecules, CD40 and CD86 was notaltered. In contrast, TRIF/TICAM-1-dependent production of type I IFN was profoundly impaired. These results demonstrate that intracellular TLR4/MD-2 is responsible for unique set of LPS responses.
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[Journal Article] Unc93B1 restricts systemic lethal inflammation by orchestrating TLR7- and TLR9-trafficking2011
Author(s)
Ryutaro Fukui, Shin-ichiro Saitoh, Atsuo Kanno, Masahiro Onji, Takuma Shibata, Akihiko Ito, Morikazu Onji, Mitsuru Matsumoto, Shizuo Akira, Nobuaki Yoshida, Kensuke Miyake
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Journal Title
Peer Reviewed
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