title: Immunomodulatory properties of pentoxifylline are mediated via adenosine-dependent pathways.
abstract: The phosphodiesterase inhibitor pentoxifylline (PTX) exerts multiple beneficial immunomodulatory effects in states of hyperinflammation. However, the exact mechanism of action still remains elusive, and the clinical effects of PTX cannot be reliably predicted. In immune cells, the G protein-coupled adenosine A2A receptor (A2AR) exerts strong anti-inflammatory effects. As PTX amplifies signaling pathways downstream of Gs protein-coupled receptors, the A2AR-signaling pathway might be involved in the mediation of immune-suppressive effects of PTX. Here, we investigated this assumption in LPS-stimulated human polymorphonuclear (PMN) leukocytes and in anti-CD3/CD28-stimulated human T cells. In stimulated PMN leukocytes, PTX treatment led to a 4.5-fold decrease of the 50% inhibitory concentrations of adenosine on the H2O2 production; i.e., for adenosine plus PTX (in clinically relevant concentrations), an overadditive increase of inhibitory effects from less than 20% (estimated for each) to 56% (+/-5%) was found. In T cells, adenosine plus PTX revealed similar synergistic inhibitory effects on proinflammatory cytokine production. Inhibition of interferon gamma and TNF-alpha production increased from 7% (+/-1%) and 31% (+/-6%) (PTX alone) to 49% (+/-2%) and 69% (+/-6%), respectively. In T cells and PMN leukocytes, mRNA transcription of the A2AR was significantly increased upon stimulation, which was not influenced by PTX. In human PMN leukocytes and T cells, clinically relevant anti-inflammatory effects of PTX can be achieved only in the presence of sufficient adenosine concentrations. Sufficient adenosine levels might be a prerequisite for the accessibility of sepsis patients to treatment with PTX.
authors.affiliation: Department of Anaesthesiology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Kreth
authors.forename: Carola
authors.initials: C
authors.lastname: Ledderose
authors.forename: Benjamin
authors.initials: B
authors.lastname: Luchting
authors.forename: Florian
authors.initials: F
authors.lastname: Weis
authors.forename: Manfred
authors.initials: M
authors.lastname: Thiel
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D000241:Adenosine; D010431:Pentoxifylline