| Project/Area Number |
11557039
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内科学一般
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| Research Institution | HYOGO COLLEGE OF MEDICINE |
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Principal Investigator |
NAKANISHI Kenji HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, PROFESSOR, 医学部, 教授 (60172350)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMURA Haruki Hyogo College of Medicine, Immunology and Medical Zoology, Professor, 医学部, 教授 (60111043)
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)
AKIRA Shizuo Osaka University, Research Institute for Microbial Diseases, Professor, 医学部, 教授 (50192919)
MIZUTANI Hitoshi Mie University, Medical School, Professor, 医学部, 教授 (30115737)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥12,900,000 (Direct Cost: ¥12,900,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2000: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1999: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | IL-18 / Cspase-1 / IgE / CD4+^T cell / KCASP1Tg / KIL-18Tg / Innate type allergy / Caspase-1 / アトピー性皮膚炎(AD) / 高IgE血症 / Caspase-1阻害剤 / アトピー様症状 / Caspase-1遺伝子トランスジェニックマウス |
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| Research Abstract |
IL-18 was discovered as a factor that enhances IFN-y production from Thl cells in the presence of anti-CD3 and IL-12.Like IL-lp, IL-18 is synthesized as a precursor protein that requires cleavage with caspase-1 to become active. As biological action of IL-18 had been investigated under the presence of IL-12, IL-18 had been rabelled as an IFN-Y inducing factor. However, we demonstrated that IL-18 causes high-level IgE production when administered to normal mice by causing CD4* T cells to produce IL-4 and to express CD40L.Atopic dermatitis (AD) is pruritic skin disease induced by the products of basophils and mast cells. As IL-18 directly stimulates these cells to produce IL-4, IL-13 and histamine, we investigated whether IL-18 can induce atopic response without being encountered with allergen or IgE induction. For this purpose, we established KCASPlTg or KIL-18Tg which over-express IL-18 or caspase-1 gene in their keratinocytes, respectively.Both types of transgenic mice produce large a
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mounts of IL-18, IgE and histamine and spontaneously develop chronic dermatitis accumulated with mast cells under SPF condition. Deletion of stat6 gene in KCASPlTg completely abrogated IgE production without eliminating their cutaneous changes, suggesting that IL-18 but not IgE induces these pathological changes. We next established KCASPlTg lacking IL-18 and found that this depletion almost completely abrogated cutaneous alternation. On the other hand, KJL-18Tg took much longer time to display these atopic phenotypes than KCASPlTg. Moreover, depletion of IL-1 gene in KCASPlTg delayed this onset. Therefore, atopic inflammation might be initiated by over-release of IL-18 and accelerated by IL-1.Our data may allow us to propose to classify atopy to allergen/ IgE-dependent atopy (acquired type allergy) and IL-18-dependent but IgE-independent atopy (innate type allergy). Furthermore, our data suggest that therapeutic approach focusing on Caspase-l/IL-18 as a target molecule will provide us a new insight into the establishment of the treatment for allergic disorder. Less
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