2004 Fiscal Year Final Research Report Summary
Analysis of signal transduction pathway in innate immunity during sepsis
| Project/Area Number |
15590349
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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 |
Experimental pathology
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| Research Institution | Kumamoto University |
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Principal Investigator |
MATSUKAWA Akihiro Kumamoto University, Pathology, Associate Prof., 大学院・医学薬学研究部, 助教授 (90264283)
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| Project Period (FY) |
2003 – 2004
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| Keywords | sepsis / innate immunity / signal transduction / cytokine / chemokine / neeutrophil / macrophage |
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| Research Abstract |
Stat3 is a transcription factor mediating anti-inflammatory properties of IL-10. To understand the role of Stat3 in inflammation, mice with targeted disruption of Stat3 in macrophages and neutrophils were succumbed to septic peritonitis. The mice displayed an excessive local and systemic inflammation relative to the control mice, an event that was accompanied by substantial increases in the level of multiple cytokines. Hepatic and renal injury was significantly exacerbated in mice with Stat3 deficiency. In addition, the mice exhibited an increased lethality after intraperitoneal inoculation of live bacteria recovered. In vitro, productions of inflammatory cytokines were significantly augmented when cells were stimulated with a synthetic lipopeptide, macrophage-activating lipopeptide-2(MALP-2) and LPS. Thus, macrophage/neutrophil-specific Stat3 is crucial in modulating multiple organ failure associated with systemic inflammation. Experiments were further carried out to understand the pr
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ecise role of Stat3 in inflammation. For this purpose, mice lacking Stat3 in macrophages and neutrophils were intraperitoneally injected with thioglycollate and the subsequent inflammatory responses were investigated. We obtained evidence that Stat3 expressed in resident macrophages, but not other cell types, play a central role in the regulation of inflammatory response. Resident macrophages are important in triggering inflammation, but the cells in the same breath appear to control inflammation through Stat3 signaling pathway.
C57BL/6 and BALB/c mice are prototypical Th1- and Th2-type mouse strains, respectively. We attempted to characterize the innate immune response of macrophages from these mouse strains. We demonstrated that macrophages from BALB/c mice showed impaired bactericidal activity relative to those from C57BL/6 mice, resulting from a lack of effector molecules for bacterial killing by the cells. Thus, innate immune response of macrophages is different between these mouse strains, which may affect the development of Th1 and Th2 adaptive immunity in these strains. In different experiments, we showed that C10, regarded as Th2-type chemokine in acquired immune response, is a potent monocyte chemoattractant in a sterile peritonitis model. Less
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