Pleurocidin, a novel antimicrobial peptide, induces human mast cell activation through the FPRL1 receptor

Abstract

Pleurocidins are a novel family of α-helical cationic antimicrobial peptides (CAPs) that are structurally and functionally similar to cathelicidins, one of the major CAP families. As cathelicidins stimulate mast cell chemotaxis and mediator release, we postulated that pleurocidins similarly activate mast cells. A screen of 20 pleurocidin peptides revealed that some were capable of degranulating the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). Pleurocidin NRC-04 caused LAD2 to adhere, migrate, degranulate, and release cysteinyl leukotrienes and prostaglandin D2. Moreover, pleurocidin increased intracellular Ca(2+) mobilization in mast cells and induced the production of proinflammatory chemokines such as monocyte chemotactic protein-1/C-C motif chemokine ligand 2 (CCL2) and macrophage inflammatory protein-1β/CCL4. Our evaluation of possible cellular mechanisms suggested that G proteins, phosphoinositol-3 kinase (PI3K), phospholipase C (PLC), and phosphokinase C (PKC) were involved in pleurocidin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G protein inhibitor), wortmanin (PI3K inhibitor), U-73122 (PLC inhibitor), and Ro-31-8220 (PKC inhibitor), respectively. We also found that human mast cells expressed the N-formyl-peptide receptor 1 (FPRL1) receptor and FPRL1-specific inhibitor affected pleurocidin-mediated activation of mast cell. Our finding that the novel CAP pleurocidin activated human mast cell through G protein-coupled receptor signaling suggests that this peptide might have immunomodulatory functions.

The Novel Receptor C5aR2 Is Required for C5a-Mediated Human Mast Cell Adhesion, Migration, and Proinflammatory Mediator Production

“…Chemoattractant GPCRs induce mast cell migration and may or may not induce mediator release (54). Antimicrobial peptides may differentially regulate the release of cytokines and chemokines (38).…”

“…Mast cell accumulation is critical in various pathophysiological conditions, including allergic reactions, atopic diseases, wound healing, tissue repair, and host defense against infection (3,38). As C5a chemoattracts HMC-1, cord blood-derived human mast cells, and skin mast cells (15), we determined whether C5a also promoted adhesion and chemotaxis of LAD2 cells.…”

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

“…Although this series of compounds didn't make it to clinical testing, it is used experimentally to determine the role of PKC in biological specimens. [50] The structurally related LY-317615 (now known as enzastaurin, Figure 11), first described by Faul et al in 2003, [51] is a PKCβ inhibitor [52] that underwent promising preclinical studies [53] as well as in a Phase I/II clinical trial, [54] but faired disappointingly in Phase III clinical trials. [55,56] The conclusion made was that enzastaurin is "unlikely to be a useful agent as a monotherapy".…”

News in Cellular Allergology: A Review of the Human Mast Cell and Basophil Granulocyte Literature from January 2013 to May 2015

“…Pleurocidin, a fish cationic antimicrobial peptide, activates mast cells to secrete CCL2 and CCL4 [23]. The human cathelithicin LL-37 activates degranulation and cytokine secretion, but not the synthesis of arachidonic acid metabolites [24].…”