Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns

  title={Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns},
  author={Esther M Speer and David J. Dowling and Lukasz S. Ozog and Jianjin Xu and Jie Yang and Geetika Kennady and Ofer Levy},
  journal={Pediatric Research},
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… 

Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro

Age, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro.

Pentoxifylline Alone or in Combination with Gentamicin or Vancomycin Inhibits Live Microbe-Induced Proinflammatory Cytokine Production in Human Cord Blood and Cord Blood Monocytes In Vitro

It is demonstrated that PTX inhibited microbe-induced proinflammatory cytokine production, especially when combined with antimicrobial agents, without enhancing microbial proliferation in human cord blood in vitro, thus supporting its utility as candidate adjunctive agent for newborn sepsis.

Cyclic AMP in human preterm infant blood is associated with increased TLR-mediated production of acute-phase and anti-inflammatory cytokines in vitro

The ontogeny of blood cAMP concentrations and associations with chorioamnionitis and TLR-mediated production of cytokines suggest that this secondary messenger helps shape distinct neonatal pathogen responses in early life.

Pentoxifylline Can Reduce the Inflammation Caused by LPS after Inhibiting Autophagy in RAW264.7 Macrophage Cells

The autophagy in cells inhibited by PTX exhibited dose- and time-dependent effects, and PTX alleviated LPS-induced inflammation caused by retarded autophagic, and in RAW264.7 macrophage cells, the data indicated that AMPK signaling perhaps functioned importantly in repressed autphagy.

Physiologically relevant aspirin concentrations trigger immunostimulatory cytokine production by human leukocytes

It is found that exogenous addition of COX downstream product, PGE2, attenuates the TLR ligand-mediated cytokine secretion by augmenting production of anti-inflammatory cytokines and inhibiting release of pro- inflammatory cytokines.

A Neonatal Murine Escherichia coli Sepsis Model Demonstrates That Adjunctive Pentoxifylline Enhances the Ratio of Anti- vs. Pro-inflammatory Cytokines in Blood and Organ Tissues

Addition of PTX to antibiotics in murine neonatal E. coli sepsis promoted an anti-inflammatory milieu through inhibition of plasma TNF and enhancement of IL-10 production in plasma and organs without increasing bacterial growth, supporting its utility as a potential adjunctive agent for newborn sepsi.

Plasma cytokine profiles in very preterm infants with late-onset sepsis

Very preterm infants have a marked innate inflammatory response at the time of LOS, and the increase in IL-10/TNF-α ratio may indicate early immune hypo-responsiveness.

Efficacy of Melatonin and Pentoxifylline combination therapy in treatment of endotoxin induced hepatic dysfunction in white albino mice

Melatonin and pentoxifylline alone and as combination therapy as effective in countering LPS induced hepatotoxicity is evaluated, however the combination therapy did not yield synergistic effects.

Emerging Role of the NLRP3 Inflammasome and Interleukin-1β in Neonates

The NLRP3 inflammasome-interleukin (IL)-1β pathway has been extensively studied in adults and pre-clinical models, improving understanding of innate immunity and offering an attractive therapeutic target that is already contributing to clinical management in many auto-inflammatory disorders.



Innate Immunity of the Human Newborn Is Polarized Toward a High Ratio of IL-6/TNF-α Production In Vitro and In Vivo

Serum collected from newborns during the first week of life demonstrates higher IL-6/TNF-α ratios than does cord blood, associated with elevations of the IL- 6-inducible acute phase reactants CRP and LPS-binding protein in the first days of life.

The Adenosine System Selectively Inhibits TLR-Mediated TNF-α Production in the Human Newborn1

It is concluded that the distinct adenosine system of newborns polarizes TLR-mediated cytokine production during the perinatal period and may thereby modulate their innate and adaptive immune responses.

Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF-α Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-8481

Impaired response to multiple TLR ligands may significantly contribute to immature neonatal immunity and relative preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.

Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells.

It is concluded that TLR8 agonists are uniquely efficacious in activating costimulatory responses in neonatal APCs and suggest that these agents are promising candidate adjuvants for enhancing immune responses in human newborns.

Immunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes: basic mechanisms and translational opportunities.

The strong agonist activities of TLR8 agonists also extend to human neonatal leucocytes, which usually display impaired Th1-polarizing responses to many diverse stimuli including agonists of other TLRs.

The Ultra-Potent and Selective TLR8 Agonist VTX-294 Activates Human Newborn and Adult Leukocytes

VTX-294 is a novel ultra-potent TLR8 agonist that activates newborn and adult leukocytes and is a candidate vaccine adjuvant in both early life and adulthood.

Innate immune activation in neonatal tracheal aspirates suggests endotoxin-driven inflammation

Correlation of endotoxin with TA inflammatory responses suggests endotoxin bioactivity and the possibility that endotoxin antagonists could mitigate pulmonary inflammation and its sequelae in this vulnerable population of critically ill neonates.