Rhesus Macaque Theta Defensins Suppress Inflammatory Cytokines and Enhance Survival in Mouse Models of Bacteremic Sepsis
Year: 2012
Type: article
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.
Source: PLoS ONE
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: University of Southern California, Southern California Clinical and Translational Science Institute, USC Norris Comprehensive Cancer Center, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Dental and Craniofacial Research, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1096387360, Los Angeles Basin Clinical and Translational Science Institute, G1214767782, G1462746016, G2236268429, G2331704211, G3166988275, G3658079094, MOLECULAR ASPECTS OF LEUKOCYTE ANTIMICROBIAL PEPTIDES, G3687380347, G3710516316, G4012934433, The Southwest National Primate Research Center, G4571653212, G4835235499, Physiologic Peptide Cyclization in Myeloid Cells, G589243345, G5895764547, PEPTIDE EFFECTORS OF ENTERIC HOST DEFENSE, Post-translational processing of myeloid alpha-defensins., G6380822270, G7654736708, STUDIES OF ALPHA-DEFENSINS IN PRIMATE INNATE IMMUNITY, G9000058728, G9000108948, G9000342024, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG), G905063056
OpenAlex ID: W1995047265