Modulation of neutrophil apoptosis in septic shock and its regulation by endogenous antimicrobial peptides
| Project/Area Number |
15590400
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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 | JUNTENDO UNIVERSITY |
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Principal Investigator |
NAGAOKA Isao Juntendo University, School of Medicine, Professor, 医学部, 教授 (60164399)
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| Co-Investigator(Kenkyū-buntansha) |
KUWAHARA Kyoko (ARAI Kyoko) Juntendo University, School of Medicine, Instructor, 医学部, 助手 (10167976)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Sepsis / Neutrophil / Apoptosis / Endotoxin / Cytokine / Monocyte / Macrophage / Toll-like receptor / Integrins |
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| Research Abstract |
Peptide antibiotics possess potent antimicrobial activities against invading microorganisms and contribute to innate host defense. We previously revealed that antibacterial cathelicidin CAP11 exerts protective actions against endotoxin shock model. During Gram-negative bacterial sepsis, LPS activates neutrophils and their apoptosis is suppressed. Prolonged presence of activated neutrophils causes uncontrolled release of toxic metabolites, leading to the systemic tissue injury. To evaluate a therapeutic potential of CAP11 for Gram-negative sepsis, we here investigated the action of CAP11 on LPS-induced suppression of neutrophil apoptosis.
LPS suppressed neutrophil apoptosis, accompanied with NF-kappaB activation, ERK phosphorylation, Bcl-XL expression and caspase 3 inhibition. Interestingly, CAP11 reversed the actions of LPS to trigger these changes, and induced neutrophil apoptosis. Furthermore, LPS activated monocytes to produce anti apoptotic cytokines (IL-1beta, TNF-alpha and IL-8) and suppressed neutrophil apoptosis. Importantly, CAP11 inhibited the cytokine production from monocytes, thereby inducing neutrophil apoptosis. Finally, CAP11 strongly suppressed LPS-binding to neutrophils and monocytes.
Thus, CAP11 is able to block the LPS-induced prolongation of neutrophil survival via the suppression of anti apoptotic signaling in neutrophils and cytokine production from monocytes by inhibiting LPS-binding to target cells. CAP11 is expected to have a therapeutic potential in Gram-negative sepsis to induce neutrophil apoptosis, thereby possibly attenuating tissue injury.
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Report
(3 results)
Research Products
(20 results)
