Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. Human antimicrobial peptides, α-defensins (human neutrophil peptides, HNPs), human β-defensins (hBDs), and cathelicidin (LL-37) not only exhibit potent bactericidal activities against Gram-negative and Gram-positive bacteria, but also function as immunomodulatory molecules by inducing cytokine and chemokine production, and inflammatory and immune cell activation. Neutrophil is a critical effector cell in host defense against microbial infection, and its lifespan is regulated by various pathogen- and host-derived substances. Here, we provided the evidence that HNP-1, hBD-3, and LL-37 cannot only destroy bacteria but also potently modulate (suppress) neutrophil apoptosis, accompanied with the phosphorylation of ERK-1/-2, the downregulation of tBid (an proapoptotic protein) and upregulation of Bcl- x L (an antiapoptotic protein), and the inhibition of mitochondrial membrane potential change and caspase 3 activity, possibly via the actions on the distinct receptors, the P2Y6 nucleotide receptor, the chemokine receptor CCR6, and the low-affinity formyl-peptide receptor FPRL1/the nucleotide receptor P2X7, respectively. Suppression of neutrophil apoptosis results in the prolongation of their lifespan and may be advantageous for the host defense against bacterial invasion. 1. Introduction Neutrophils play an important role as an effector of inflammation, tissue injury, and host defense against microbial infection [1]. The lifetime of neutrophils, terminally differentiated blood cells, is relatively short, and they constitutively undergo apoptosis [1]. Apoptotic neutrophils are phagocytosed by macrophages without release of proinflammatory mediators, leading to the limitation of tissue injury and resolution of inflammatory process [2–4]. In this context, it is interesting to note that spontaneous apoptosis of neutrophils is inhibited in patients with sepsis, systemic inflammatory syndrome (SIRS), and acute respiratory distress syndrome (ARDS) by the action of various pathogen- and host-derived substances, such as bacterial products (i.e., Gram-negative lipopolysaccharide; LPS), cytokines, and chemokines (i.e., IL-1β and IL-8) [3, 5–8]. The suppressed neutrophil apoptosis results in the prolongation of their life span and causes the uncontrolled release of cytotoxic metabolites and proinflammatory substances (i.e., reactive oxygen species and proteases), which leads to the amplification of systemic inflammation, tissue injury,
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