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Posttranslational Processing: A Novel Role Beyond Innate Immunity
Department of Antibacterials, Immunology, and Inflammation, Pfizer Global Research and Development, Pfizer, Inc., Groton, CT 06340
Human monocytes stimulated with LPS produce large quantities of
prointerleukin-1
, 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-1
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-1. The
PTG-mediated response engaged a mechanism similar to that initiated by
extracellular ATP acting via the P2X7 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-1 posttranslational processing. The human defensin
HNP-1 and the frog peptide magainin 1 elicited export of 17-kDa
IL-1, but these agents were less efficient than PTGs. As a result of
this ability to promote release of potent proinflammatory cytokines
such as IL-1, select antimicrobial peptides may possess important
immunomodulatory functions that extend beyond innate
immunity.
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