Modulation of Cytokine Signals and Treatment for Inflammatory Lung Diseases
| Project/Area Number |
17390243
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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 | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
INOUE Hiromasa Kyushu University, Hospital, Assistant Professor, 病院, 講師 (30264039)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Koichiro Kyushu University, Hospital, Research Associate, 病院・助手 (60325462)
KUBO Masato RIKEN Yokohama Institute, Research Center for Allergy and Immunology, Team Leader, 免疫アレルギー科学総合研究センター, チームリーダー (40277281)
SAKUDA Shohei The University of Tokyo, Department of Applied Biological Chemistry, Associate Professor, 大学院農学生命科学研究科, 准教授 (80192087)
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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 |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2005: ¥9,500,000 (Direct Cost: ¥9,500,000)
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| Keywords | cytokine / Th2 / SOCS / asthma / COPD / Th3 |
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| Research Abstract |
T helper 2 (Th2) cytokines, such as interleukin (IL)-4,IL-5,and IL-13,play an important role in pathophysiology of allergic asthma. Suppressors of cytokine signaling (SOCSs) are negative feedback regulators of Jak/STAT cytokine signaling. We have demonstrated that overexpression of SOCS-3,a negative regulators for cytokine signaling, in T cells enhances Th2 development, and augments airway hyperresponsiveness and eosinophil accumulation in a murine model of allergic asthma. Human studies indicate that pathologically high levels of SOCS3 expression in T cells relate to allergic diseases.
To define the physiological roles of SOCS3 in T cells, we generated T cell-specific SOCS3 conditional knockout (cKO) mice. SOCS3-cKO mice showed reduced responses to OVA-induced airway hyperresponsiveness in a Th2-type asthma model. In Th2 and Th3 skewing conditions, SOCS3-deficient CD4^+ T cells produced higher levels of TGF-β1 and IL-10,but lower levels of IL-4,than WT CD4^+ T cells. Thus, we found that SOCS3 reciprocally modulate Th3 differentiation characterized by the production of TGF-β1 and IL-10.
To clarify whether down-regulation of SOCS-3 expression inhibits allergic asthma, we studied ovalbumin (OVA)-induced Th2 differentiation in CD4^+T cells from SOCS3-heterozygous deleted (SOCS3^<+/->) DO 11.10 mice and from SOCS3^<+/+> X DO 11.10 mice. The efficiency of Th2 development in T cells from SOCS3^<+/->X DO11.10 mice was markedly reduced compared to that in SOCS3^<+/+> X DO 11.10 mice.
These studies suggest that therapies modulating SOCS-3 expression in T cells might be effective in control of allergic disorders, including severe asthma.
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Report
(3 results)
Research Products
(16 results)
