| Budget Amount *help |
¥3,740,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥240,000)
Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. An antibacterial cathelicidin, human LL-37 and hBDs (human B-defensins) not only exhibits potent bactericidal activities but also functions as a chemoattractant for immune cells including neutrophils. During bacterial infections including sepsis, the lifespan of neutrophils is regulated by various pathogen and host-derived substances. Here, to further evaluate the role of LL-37 and hBDs in innate immunity, we investigated their actions on neutrophil apoptosis.
Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, LL-37 and HBD-3 suppressed neutrophil apoptosis, accompanied with the phosphorylation of ERK-1/-2, expression of Bcl-XL (an anti-apoptotic protein) and inhibition of caspase 3 activity. Interestingly, LL-37- and hBD-3-induced suppression of neutrophil apoptosis was attenuated by the antagonists for formyl-peptide receptor-like 1 (FPRL1) and P2X7 nucleotide receptor, and a chemokine receptor CCR6, respectively.
Collectively, these observations indicate that LL-37 and hBD-3 can not only kill bacteria but also modulate (suppress) neutrophil apoptosis via the activation of FPRL1 and P2X7, and CCR6, respectively, in bacterial infections. Suppression of neutrophil apoptosis results in the prolongation of their life span and may be advantageous for host defense against bacterial invasion. However, the suppressed neutrophil apoptosis may causes the uncontrolled release of cytotoxic metabolites and pro-inflammatory substances (i.e. reactive oxygen species and proteases), which leads to the amplification of systemic inflammation, tissue injury and organ failure observed in sepsis.
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