title: Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns.
abstract: BACKGROUND
  Toll-like receptor (TLR)-mediated inflammation may contribute to neonatal sepsis, for which pentoxifylline (PTX), a phosphodiesterase inhibitor that raises intracellular cAMP, is a candidate adjunctive therapy. We characterized the anti-inflammatory effects of PTX toward TLR-mediated production of inflammatory (tumor necrosis factor (TNF) and interleukin (IL)-1β) and proresolution (IL-6 and IL-10) cytokines in human newborn and adult blood.
  
  
  METHODS
  Newborn cord and adult blood were treated with PTX (50-400 µmol/l) before, during or after stimulation with LPS (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/ATP (inflammasome activation). Cytokines were measured by multiplex assay (supernatants), intracellular cytokines and signaling molecules by flow cytometry, and mRNA by quantitative real-time PCR.
  
  
  RESULTS
  Whether added 2 h pre-, simultaneously to, or 2 h post-TLR stimulation, PTX inhibited TLR-mediated cytokine production in a concentration-dependent manner, with greater efficacy and potency in newborn blood, decreasing intracellular TNF and IL-1β with relative preservation of IL-10 and IL-6. PTX decreased TLR-mediated TNF mRNA while increasing IL-10 mRNA. Neonatal plasma factors contributed to the anti-inflammatory effects of PTX in newborn blood that were independent of soluble TNF receptor concentrations, p38 MAPK phosphorylation and IĸB degradation.
  
  
  CONCLUSIONS
  PTX is a potent and efficacious inhibitor of TLR-mediated inflammatory cytokines in newborn cord blood and a promising neonatal anti-inflammatory agent.
authors.affiliation: Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Speer
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: David J
authors.initials: DJ
authors.lastname: Dowling
authors.affiliation: Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Lukasz S
authors.initials: LS
authors.lastname: Ozog
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Jianjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Family, Population, and Preventive Medicine Department, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors.forename: Geetika
authors.initials: G
authors.lastname: Kennady
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Precision Vaccines Program, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D000367:Age Factors; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007231:Infant, Newborn; D058847:Inflammasomes / Q000097:blood* / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D010431:Pentoxifylline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000097:blood; D013997:Time Factors; D051193:Toll-Like Receptors / Q000097:blood* / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; C508609:IL10 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D007093:Imidazoles; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000255:Adenosine Triphosphate; D010431:Pentoxifylline; C402365:resiquimod