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Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns
- Source :
- Pediatric Research. 81:806-816
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- 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. 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. 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. PTX is a potent and efficacious inhibitor of TLR-mediated inflammatory cytokines in newborn cord blood and a promising neonatal anti-inflammatory agent.
- Subjects :
- Adult
Lipopolysaccharides
0301 basic medicine
Time Factors
Inflammasomes
medicine.medical_treatment
Interleukin-1beta
Anti-Inflammatory Agents
Inflammation
Pharmacology
Pentoxifylline
Proinflammatory cytokine
03 medical and health sciences
Adenosine Triphosphate
0302 clinical medicine
medicine
Humans
RNA, Messenger
Dose-Response Relationship, Drug
Interleukin-6
Tumor Necrosis Factor-alpha
business.industry
Toll-Like Receptors
Age Factors
Imidazoles
Infant, Newborn
Interleukin
Inflammasome
Fetal Blood
Interleukin-10
030104 developmental biology
Cytokine
Pediatrics, Perinatology and Child Health
TLR4
Tumor necrosis factor alpha
Inflammation Mediators
medicine.symptom
business
Biomarkers
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15300447 and 00313998
- Volume :
- 81
- Database :
- OpenAIRE
- Journal :
- Pediatric Research
- Accession number :
- edsair.doi.dedup.....68fb671f6564c3cfdce3971f89a1a0bf
- Full Text :
- https://doi.org/10.1038/pr.2017.6