Evaluation of the effects of peptide antibiotics human β‐defensins‐1/‐2 and LL‐37 on histamine release and prostaglandin D₂production from mast cells

Abstract

Antimicrobial peptides, human β‐defensins (hBD‐1/‐2), and LL‐37 (a peptide of human cathelicidin CAP18) are predominately expressed at epithelial tissues, where they participate in the innate host defense by killing invading microorganisms. In this study, to investigate the interactions between epithelial cell‐derived antimicrobial peptides and mast cells, we evaluated the effects ofhBD‐1/‐2 and LL‐37 on mast cell functions using rat peritoneal mast cells. hBD‐2 and LL‐37 but not hBD‐1 induced histamine release and intracellular Ca2+ mobilization, and hBD‐2 was more potent than LL‐37. Interestingly, histamine release and intracellular Ca2+ mobilization elicited by hBD‐2 and LL‐37 were markedly suppressed by BAPTA‐AM (an intracellular Ca2+ chelating agent), pertussis toxin and U‐73122 (a phospholipase C inhibitor). In addition, among the peptides examined, only hBD‐2 significantly induced PGD2 production, which was abolished by indomethacin (cyclooxygenase‐1/‐2 inhibitor) but not NS‐398 (cyclooxygenase‐2 inhibitor), suggesting that hBD‐2‐induced PGD2 production is mediated by cyclooxygenase‐1. Likewise, the PGD2 production was suppressed by pertussis toxin and U‐73122. These observations suggest that hBD‐2 and LL‐37 stimulate mast cells to mobilize intracellular Ca2+ and release histamine or generate PGD2 in a G protein‐phospholipase C‐dependent manner. Thus, hBD‐2 and LL‐37 may have modulatory effects on inflammatory reactions.

Novel Insight Into the Role of Antimicrobial (Host Defense) Peptides/Proteins in Human Skin Diseases

“…LL-37-mediated pro-inflammatory responses include the downregulation of IL-10, upregulation of IL-1β, IL-12p40, IL-18, and cooperation with IL-1β to enhance the induction of inflammatory mediators 43) . LL-37 also induces mast cell degranulation, the production of lipid mediators and pruritogenic factors, and increases vascular permeability 19) 20) 44) . LL-37-mediated anti-inflammatory responses include the inhibition of IFN-γ, TNF-α, IL-4 and IL-12 production 43) .…”

Innate Immune Defense System of the Skin

“…[54][55][56] LL-37 also induces histamine release from mast cells and intracellular Ca 2+ mobilization. 57 Cathelicidin may help repair skin wounds by inducing keratinocyte migration via transactivation of the epidermal growth factor receptor. 58 LL-37 significantly inhibits the lipopolysaccharide-induced release of proinflammatory cytokines by macrophages.…”

Innate defences against methicillin‐resistant Staphylococcus aureus (MRSA) infection

“…They include being a chemotactic factor for CCR6 dendritic cells, degranulation of mast cells, and induction of the production of prostaglandin D2 [45,47,86,87].…”