Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2and LL-37 on histamine release and prostaglandin D-2 production from mast cells

Antimicrobial peptides, human beta -defensins (hBD-1/-2), and LL-37 (a pept ide of human cathelicidin CAP18) are predominately expressed at epithelial tissues, where they participate in the innate host defense by killing invad ing microorganisms. In this study, to investigate the interactions between epithelial cell-derived antimicrobial peptides and mast cells, we evaluated the effects of hBD-1/-2 and LL-37 on mast cell functions using rat periton eal 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. Int erestingly, histamine release and intracellular Ca2+ mobilization elicited by hBD-2 and LL-37 were markedly suppressed by BAPTA-AM (an intracellular C a2+ chelating agent), pertussis toxin and U-73122 (a phospholipase C inhibi tor). In addition, among the peptides examined, only hBD-2 significantly in duced PGD(2) production, which was abolished by indomethacin (cyclooxygenas e-1/-2 inhibitor) but not NS-398 (cyclooxygenase-2 inhibitor), suggesting t hat hBD-2-induced PGD, production is mediated by cyclooxygenase-l. Likewise , the PGD(2) production was suppressed by pertussis toxin and U-73122. Thes e observations suggest that hBD-2 and LL-37 stimulate mast cells to mobiliz e intracellular Ca2+ and release histamine or generate PGD(2) in a G protei n-phospholipase C-dependent manner. Thus, hBD-2 and LL-37 may have modulato ry effects on inflammatory reactions.