Modulation of neutrophil apoptosis in septic shock and its regulation by endogenous antimicrobial peptides

肽类抗生素对入侵的微生物具有有效的抗菌活性，并有助于宿主的先天防御。我们以前发现，抗菌cathelicidin CAP 11发挥保护作用，对内毒素休克模型。在革兰氏阴性细菌脓毒症期间，LPS激活中性粒细胞并且其凋亡被抑制。活化的中性粒细胞的长期存在导致毒性代谢物的不受控制的释放，导致全身组织损伤。为了评价CAP 11对革兰氏阴性脓毒症的治疗潜力，我们在此研究了CAP 11对LPS诱导的中性粒细胞凋亡抑制的作用，LPS抑制中性粒细胞凋亡，伴随着NF-κ B激活、ERK磷酸化、Bcl-XL表达和caspase 3抑制。有趣的是，CAP 11逆转了LPS触发这些变化的作用，并诱导中性粒细胞凋亡。此外，LPS激活单核细胞产生抗凋亡细胞因子（IL-1 β、TNF-α和IL-8）并抑制中性粒细胞凋亡。重要的是，CAP 11抑制单核细胞产生细胞因子，从而诱导中性粒细胞凋亡。最后，CAP 11强烈抑制LPS与中性粒细胞和单核细胞的结合，因此，CAP 11能够通过抑制中性粒细胞中的抗凋亡信号和单核细胞的细胞因子产生来阻断LPS诱导的中性粒细胞存活的延长。CAP 11有望在革兰氏阴性脓毒症中具有治疗潜力，以诱导中性粒细胞凋亡，从而可能减轻组织损伤。

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.