The human cationic host defense peptide LL-37 mediates contrasting effects on apoptotic pathways in different primary cells of the innate immune system

Abstract

The human cathelicidin LL-37 is a cationic host defense peptide (antimicrobial peptide) expressed primarily by neutrophils and epithelial cells. This peptide, up-regulated under conditions of inflammation, has immunomodulatory and antimicrobial functions. We demonstrate that LL-37 is a potent inhibitor of human neutrophil apoptosis, signaling through P2X 7 receptors and G-proteincoupled receptors other than the formyl peptide receptor-like-1 molecule. This process involved modulation of Mcl-1 expression, inhibition of BID and procaspase-3 cleavage, and the activation of phosphatidylinositol-3 kinase but not the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. In contrast to the inhibition of neutrophil apoptosis, LL-37 induced apoptosis in primary airway epithelial cells, demonstrating alternate consequences of LL-37-mediated modulation of apoptotic pathways in different human primary cells. We propose that these novel immunomodulatory properties of LL-37 contribute to peptide-mediated enhancement of innate host defenses against acute infection and are of considerable significance in the development of such peptides and their synthetic analogs as potential therapeutics for use against multiple antibioticresistant infectious diseases.

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…Mononuclear cell layers were collected, washed twice in PBS, and the cells seeded at 1 3 10 6 cells/ml in RPMI 1640 with 10% heat-inactivated FCS, 2 mM L-glutamine, and 1 mM sodium pyruvate (all from Invitrogen), in a humidified incubator at 37˚C and 5% CO 2 . Neutrophils were isolated as previously described (10). Blood was prediluted in 2% (w/v) Dextran T-500 (Amersham Biosciences) in 0.9% saline and sedimented for 30 min at room temperature.…”

“…The microbicidal activity of peptides is due to their preferential interactions with prokaryotic membranes, leading to bacterial membrane disruption and/or targeting of intracellular bacterial molecules (5,6). The immunomodulatory activities of such peptides are extremely diverse and include stimulation of chemotaxis and chemokine production (7,8), promotion of leukocyte antimicrobial functions (9), regulation of neutrophil and epithelial cell apoptosis (10,11), regulation of dendritic cell differentiation and activation, stimulation of epithelial cell migration and wound healing, promotion of angiogenesis, and many others (reviewed in Refs. 12,13).…”

Orthodontic mechanotransduction and the role of the P2X7 receptor

“…P2X7R KO-derived macrophages do not release IL-1 in response to ATP, resulting on an attenuated acute inflammatory response (Labasi et al, 2002;Lister et al, 2007). Normal function of the P2X7R results in an optimal acute phase response that extends the life cycle of neutrophils (Barlow et al, 2006). An inefficient acute response can lead to an overwhelming chronic response: massive macrophage infiltration, abundant apoptotic and necrotic cells, and generalized tissue damage (Lister et al, 2007).…”

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

“…LL-37 is found in the secondary granules of neutrophils (7), is endogenously expressed by a variety of cells including keratinocytes and epithelial cells, and is released in response to multiple inflammatory stimuli (8,9). On release, LL-37 acts as an effector molecule of innate immunity, displaying anti-infective and immunomodulatory activities, including the induction of neutrophil, CD4 + T-cell and monocyte chemotaxis (10), mast cell activation (11), and neutrophil survival (12,13). However, a concentration of 100 μg/mL of LL-37 resulted in the death of 60% untransformed human airway epithelial cells (14).…”

“…However, a concentration of 100 μg/mL of LL-37 resulted in the death of 60% untransformed human airway epithelial cells (14). These variations in the cytotoxic nature of LL-37 may potentially be related to peptide-mediated augmentation of innate immunity (13). The ability of LL-37 to promote or inhibit apoptosis depending on the cell type, and the knowledge of other cationic host defense peptides that can kill cancer cells, has led researchers to try and understand the effect(s) of LL-37 on human tumor cells.…”