title: Antimicrobial peptides initiate IL-1 beta posttranslational processing: a novel role beyond innate immunity.
abstract: Human monocytes stimulated with LPS produce large quantities of prointerleukin-1beta, but little of this cytokine product is released extracellularly as the mature biologically active species. To demonstrate efficient proteolytic cleavage and export, cytokine-producing cells require a secondary effector stimulus. In an attempt to identify agents that may serve as initiators of IL-1beta posttranslational processing in vivo, LPS-activated human monocytes were treated with several individual antimicrobial peptides. Two peptides derived from porcine neutrophils, protegrin (PTG)-1 and PTG-3, promoted rapid and efficient release of mature IL-1beta. The PTG-mediated response engaged a mechanism similar to that initiated by extracellular ATP acting via the P2X(7) receptor. Thus, both processes were disrupted by a caspase inhibitor, both were sensitive to ethacrynic acid and CP-424,174, two pharmacological agents that suppress posttranslational processing, and both were negated by elevation of extracellular potassium. Moreover, the PTGs, like ATP, promoted a dramatic change in monocyte morphology and a loss of membrane latency. The PTG response was concentration dependent and was influenced profoundly by components within the culture medium. In contrast, porcine neutrophil antimicrobial peptides PR-26 and PR-39 did not initiate IL-1beta posttranslational processing. The human defensin HNP-1 and the frog peptide magainin 1 elicited export of 17-kDa IL-1beta, but these agents were less efficient than PTGs. As a result of this ability to promote release of potent proinflammatory cytokines such as IL-1beta, select antimicrobial peptides may possess important immunomodulatory functions that extend beyond innate immunity.
authors.affiliation: Department of Antibacterials, Pfizer Global Research and Development, Pfizer, Inc., Groton, CT 06340, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Perregaux
authors.forename: Kanan
authors.initials: K
authors.lastname: Bhavsar
authors.forename: Len
authors.initials: L
authors.lastname: Contillo
authors.forename: Jishu
authors.initials: J
authors.lastname: Shi
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gabel
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D061945:Caspase Inhibitors; D048429:Cell Size / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010455:Peptides / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects* / Q000276:immunology*; D011506:Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D029867:Xenopus Proteins; D023084:alpha-Defensins / Q000494:pharmacology; D023083:beta-Defensins / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C406407:DEFB1 protein, human; C106641:DEFB4A protein, human; D007375:Interleukin-1; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D010455:Peptides; D011506:Proteins; D029867:Xenopus Proteins; D023084:alpha-Defensins; D023083:beta-Defensins; C406413:human neutrophil peptide 1; C094880:protegrin-1; C094881:protegrin-3; C053300:magainin 1 peptide, Xenopus; D000255:Adenosine Triphosphate; D004976:Ethacrynic Acid