title: Rhesus macaque theta defensins suppress inflammatory cytokines and enhance survival in mouse models of bacteremic sepsis.
abstract: Theta-defensins (θ-defensins) are macrocyclic antimicrobial peptides expressed in leukocytes of Old World monkeys. The peptides are broad spectrum microbicides in vitro and numerous θ-defensin isoforms have been identified in granulocytes of rhesus macaques and Olive baboons. Several mammalian α- and β-defensins, genetically related to θ-defensins, have proinflammatory and immune-activating properties that bridge innate and acquired immunity. In the current study we analyzed the immunoregulatory properties of rhesus θ-defensins 1-5 (RTDs 1-5). RTD-1, the most abundant θ-defensin in macaques, reduced the levels of TNF, IL-1α, IL-1β, IL-6, and IL-8 secreted by blood leukocytes stimulated by several TLR agonists. RTDs 1-5 suppressed levels of soluble TNF released by bacteria- or LPS-stimulated blood leukocytes and THP-1 monocytes. Despite their highly conserved conformation and amino acid sequences, the anti-TNF activities of RTDs 1-5 varied by as much as 10-fold. Systemically administered RTD-1 was non-toxic for BALB/c mice, and escalating intravenous doses were well tolerated and non-immunogenic in adult chimpanzees. The peptide was highly stable in serum and plasma. Single dose administration of RTD-1 at 5 mg/kg significantly improved survival of BALB/c mice with E. coli peritonitis and cecal ligation-and-puncture induced polymicrobial sepsis. Peptide treatment reduced serum levels of several inflammatory cytokines/chemokines in bacteremic animals. Collectively, these results indicate that the anti-inflammatory properties of θ-defensins in vitro and in vivo are mediated by the suppression of numerous proinflammatory cytokines and blockade of TNF release may be a primary effect.
authors.affiliation: Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Schaal
authors.forename: Dat
authors.initials: D
authors.lastname: Tran
authors.forename: Patti
authors.initials: P
authors.lastname: Tran
authors.forename: George
authors.initials: G
authors.lastname: Ösapay
authors.forename: Katie
authors.initials: K
authors.lastname: Trinh
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Roberts
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Brasky
authors.forename: Prasad
authors.initials: P
authors.lastname: Tongaonkar
authors.forename: André J
authors.initials: AJ
authors.lastname: Ouellette
authors.forename: Michael E
authors.initials: ME
authors.lastname: Selsted
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000097:blood; D023082:Defensins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D002679:Pan troglodytes; D020033:Protein Isoforms / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology*
chemical_list: D016207:Cytokines; D023082:Defensins; D020033:Protein Isoforms; C435493:RTD-2 protein, Macaca mulatta