摘要
Peptide antibiotics possess potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. We previously revealed that antibacterial cathelicidin CAP11 (cationic antibacterial polypeptide of 11 kDa) exhibits protective actions against endotoxin shock model. During Gram-negative bacterial sepsis, lipopolysaccharide (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. In this study, we investigate the action of CAP11 on LPS-induced suppression of neutrophil apoptosis using human neutrophils.
LPS suppressed neutrophil apoptosis, accompanied with the activation of NF-κB, phosphorylation of extracellular signal-related protein kinase, expression of Bcl-XL and inhibition of caspase 3 activation. 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-1β, TNF-α and IL-8) and suppressed neutrophil apoptosis. Importantly, CAP11 inhibited the cytokine production from LPS-stimulated monocytes, and induced neutrophil apoptosis. Finally, CAP11 strongly suppressed the LPS-binding to neutrophils and monocytes. These observations indicate that CAP11 can block the LPS-induced prolongation of neutrophil survival via the suppression of anti-apoptotic signaling in neutrophils and anti-apoptotic cytokine production from monocytes by inhibiting the binding of LPS to target cells.
摘要译文
肽类抗生素具有抗入侵微生物有效的抗菌活性，有助于先天宿主防御。我们以前发现，抗菌抗菌肽CAP11（11 kDa的阳离子抗菌多肽）具有抗内毒素休克模型的保护措施。在革兰氏阴性菌败血症，脂多糖（LPS）激活的中性粒细胞和它们的细胞凋亡受到抑制。活化的中性粒细胞的长期存在引起的毒性代谢物的不受控制的释放，从而导致全身组织损伤。在这项研究中，我们调查CAP11的使用抑制了中性粒细胞凋亡人类neutrophils.LPS中性粒细胞凋亡的LPS诱导的抑制的作用下，伴随有NF-κB的活化，磷酸化细胞外信号相关的蛋白激酶，Bcl-xL的表达和抑制胱天蛋白酶3的活化。有趣的是，CAP11逆转LPS的行动引发这些变化，并诱导中性粒细胞凋亡。另外，LPS激活单核细胞产生的抗凋亡细胞因子（IL-1β，TNF-α和IL-8）和抑制嗜中性粒细胞的细胞凋亡。重要的是，CAP11抑制细胞因子的产生，从LPS刺激的单核细胞和中性粒细胞的细胞凋亡。最后，CAP11强烈抑制脂多糖结合，以中性粒细胞和单核细胞。通过抗凋亡信号在中性粒细胞和抗凋亡因子的产生，从单核细胞中，通过抑制LPS的结合到靶细胞的抑制嗜中性粒细胞存活的rolongation。
Isao Nagaoka[1]; Shin Yomogida[1]; Hiroshi Tamura[2];Michimasa Hirata[3]. Modulation of LPS-induced suppression of neutrophil apoptosis by antibacterial cathelicidin peptide CAP11[J]. Ensho Saisei, 2004,24(3): 166-172