Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns
| Autor: | Lukasz S. Ozog, Esther M. Speer, David J. Dowling, Jie Yang, Ofer Levy, Geetika Kennady, Jianjin Xu |
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| Rok vydání: | 2017 |
| Předmět: |
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 |
| Zdroj: | Pediatric Research. 81:806-816 |
| ISSN: | 1530-0447 0031-3998 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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