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.

Cellular and molecular mechanisms of pentoxifylline's beneficial effects in experimental polycystic ovary

“…As a methylxanthine derivative with a nonselective PDE inhibitory function, PTX has a wide scope of medical applications. For example, various surveys have shown multiple beneficial effects of PTX in hyperinflammation [37], suppression of OS [15,16], improvement of various ROS-related tissue injury models in which conventional antioxidants were not very effective [38,39]. It also improves fertility and increases clinical pregnancy rate through its antioxidant trait [1].…”

Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation

“…For that purpose, we used a speciWc anti-TNF-antibody, inXiximab, and thalidomide, which has been reported to inhibit the production of TNF- [35][36][37][38][39] and to inhibit NO eVects in immunological diseases [40,41]. We also used pentoxifylline, which exerts multiple beneWcial immunomodulatory eVects through the downregulation of TNFsynthesis, decreasing in IFN-, granulocyte-macrophage colony-stimulating factor, and IL-6 secretion, and by attenuating cell surface expression of the IL-2 receptor (reviewed by Kreth et al [42]). In addition to that, pentoxifylline also suppress iNOS at the mRNA level [43,44].…”

Role of pentoxifylline in non-alcoholic fatty liver disease in high-fat diet-induced obesity in mice

“…We hypothesize that metabolic status, liver metabolism, adiposity or inflammation degree can interfere with the pentoxifylline response, which could explain the controversial data obtained in different clinical studies of NAFLD patients. In this line of reasoning, pentoxifylline is effective in states of hyperinflammation because relevant anti-inflammatory effects can be achieved only in the presence of sufficient adenosine concentrations [25] . Metabolic stress, hypoxia and inflammation are conditions related to increase adenosine extracellular concentrations [26] , and thus, could interfere with the pentoxifylline response.…”