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.

Autor: Speer EM; Department of Pediatrics, Division of Neonatology, Stony Brook University School of Medicine, Stony Brook, New York, United States of America., Dowling DJ; Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America., Xu J; Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America., Ozog LS; Department of Pediatrics, Division of Neonatology, Stony Brook University School of Medicine, Stony Brook, New York, United States of America., Mathew JA; Department of Pediatrics, Division of Neonatology, Stony Brook University School of Medicine, Stony Brook, New York, United States of America., Chander A; Department of Pediatrics, Division of Neonatology, Stony Brook University School of Medicine, Stony Brook, New York, United States of America., Yin D; Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York, United States of America., Levy O; Department of Medicine, Division of Infectious Diseases, Boston Children's Hospital, Boston, Massachusetts, United States of America.; Harvard Medical School, Boston, Massachusetts, United States of America.; Precision Vaccine Program, Boston Children's Hospital, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2018 May 01; Vol. 13 (5), pp. e0196352. Date of Electronic Publication: 2018 May 01 (Print Publication: 2018).
DOI: 10.1371/journal.pone.0196352
Abstrakt: Introduction: Neonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production.
Methods: Whole newborn and adult blood was treated with PTX (50-200 μM), DEX (10-10-10-7 M), or AZI (2.5-20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity.
Results: PTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA.
Conclusions: 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. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity.
Databáze: MEDLINE
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