| Project/Area Number |
10470071
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Bacteriology (including Mycology)
|
|---|
| Research Institution | HYOGO COLLEGE OF MEDICINE |
|---|
Principal Investigator |
NAKANISHI Kenji HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, PROFESSOR, 医学部, 教授 (60172350)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YOSHIMOTO Tomohiro HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, ASSOCIATE PROFESSOR, 医学部, 助教授 (60241171)
TSUTSUI Hiroko HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, ASSOCIATE PROFESSOR, 医学部, 助教授 (40236914)
OKAMURA Haruki HYOGO COLLEGE OF MEDICINE, INSTITUTE FOR ADVANCED MEDICIAL SCIENCES, PROFESSOR, 医学部, 教授 (60111043)
AKIRA Shizuo OSAKA UNIVERSITY, RESEARCHINSTITUTE FOR MICROBIAL DISEASES, PROFESSOR, 医学部, 教授 (50192919)
KASHIWAMURA Shin-ichiro HYOGO COLLEGE OF MEDICINE, INSTITUTE FOR ADVANCED MADICAL SCIENCES, ASSISTANT PROFESSOR, 医学部, 講師 (00185761)
|
|---|
| Project Period (FY) |
1998 – 1999
|
| Project Status |
Completed (Fiscal Year 1999)
|
| Budget Amount *help |
¥8,300,000 (Direct Cost: ¥8,300,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥5,300,000 (Direct Cost: ¥5,300,000)
|
|---|
| Keywords | interleukin 18 / LPS-induced liver injury / caspase-1-deficient mice / IL-18-deficient mice / Fas ligand / 劇症肝炎 / caspase-1 / エンドトキシン / 肝炎 / IL-12 / IL-18 / FasL / TNF-α |
|---|
| Research Abstract |
Murine IL-18 is constitutively produced and stored as a biologically inactive precursor, and pro-IL-18 is cleaved into biologically active mature IL-18 by enzymes that become active under proper stimulation. We studied pathological roles of IL-18 for LPS-induced liver injury. Mice subsequently treated with Propionibacterium acnes (P.acnes) and LPS suffer from liver injury. Coinjection of anti-IL-18 and LPS protects this liver. Furthermore, casapase-1 deficient(-/-) mice or IL-18-/- mice are resistant to this sequential treatments. These results strongly indicated the involvement of IL-18 in this LPS-induced liver injury. Indeed, injection of IL-18 instead of LPS also induced liver injury in P.acnes-pretreated mice. Since IL-18 induces IFN-γ, TNF and FasL either directly or indirectly, we assumed these molecules are responsible for inducing liver injury in these P.acnes-pretreated mice. Injection of FasL as a from of membrane bound (LNK cells) or soluble form induces liver injury in P.acnes-pretreated mice. Importantly, administration of soluble FasL induces acute liver injury in P.acnes-pretreated caspase-1 -/- mice but does not do so in P.acnes-pretreated IL-18 -/- mice, indicating the IL-18 release in a caspase-independent fashion is essential for this liver injury. Therefore, positive feedback loop between FasL and IL-18 plays an important role in pathogenesis of LPS liver injury.
|
