| Project/Area Number |
17590397
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Bacteriology (including Mycology)
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| Research Institution | Jichi Medical University |
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Principal Investigator |
MATSUURA Motohiro Jichi Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (20150089)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Shinji Jichi Medical University, School of Medicine, Instructor, 医学部, 助手 (50195989)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | lipopolysaccharide (LPS) / endotoxin / regulation of IL-12 expression / LPS antagonist |
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| Research Abstract |
Lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria, is recognized by TLR4 on host immune cells to activate innate immunity leading to beneficial effects to the host. However, activation of immune reactions by LPS sometimes proceeds so strong that harmful effects are induced to the host. In the present study, regulatory mechanisms to prevent such over-activations were investigated.
Activities of LPS are expressed via actions of various mediators. IL-12 is a representative LPS-mediator and, by itself, it exhibits beneficial effects when produced properly while harmful effects when produced too much. We have found a regulatory mechanism of LPS-induced IL-12 production that activate a repressor element, GA-12, in the promoter region of IL-12p40 gene. It was indicated that hyper-activation of ERK pathway via TLR4 is required prior to activation of GA-12. When mouse peritoneal exudate cells were stimulated with a high dose LPS (1,000 ng/ml), activation of this pathway was observed and production of IL-12p40 decreased from that of optimal LPS (10 ng/ml) stimulation. These results indicated that this regulatory mechanism is functioning generally to control excessive production of IL-12.
We have also found a natural LPS-antagonist. LPS obtained from Yersinia cultured at 27℃ (optimal growth temperature) was active as LPS-agonist but LPS obtained from the bacteria cultured at 37℃ (host body temperature) was not active to human cells and showed strong antagonistic activity. Number of acyl groups in lipid A part of the LPS-37℃ was decreased from that of the LPS-27℃. This antagonistic type of the LPS-37℃ was likely to suppress all the signals downstream of TLR4 by interfering with the dimerization of TLR4.
Investigations of suppressive mechanisms in both initiation steps of LPS signaling and down stream steps for production of each LPS-mediator may be useful for development of preventive measures against harmful LPS actions.
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