Multiple organ failure (MOF) is the cause of 50 percent to 80 percent of all deaths in surgical intensive care units. MOF is documented to occur after a number of diverse clinical conditions, including mechanical and thermal trauma, pancreatitis and shock. In a large subgroup of patients, secondary infections serve to trigger the development of MOF, which is related to the development of an excessive compensatory anti-inflammatory reaction (CARS) and a generalized immunosuppressive state. CARS is characterized by several changes in the patients' immune phenotype. Two of the most important of these immune-phenotypic changes are a shift in T helper (Th) cell population from a Th1 to a Th2 response and shift in the macrophage phenotype from a proinflammatory to an anti-inflammatory one. This shift in the macrophage phenotype is characterized by a decrease in the production of IL-12 and an increase in the production of IL-10. Neither the signals nor mechanisms responsible for the development of this altered immune phenotype have been fully elucidated. Recently, it has been proposed that this immunosuppressed state may be secondary to the excessive release of a variety of mediators including catecholamines and glucocorticoids by activation of the stress system. In addition, it appears that adenosine (ADO), another stress mediator released excessively during CARS, could also contribute to the immune paralysis seen in CARS, since ADO appears to potentiate the development of an immune compromised state. Using an anti-CD3- stimulated mouse spleen cell system, we have recently discovered that extracellular ADO augments the production of the Th2 cytokine IL-4, whereas it reduces the production of the Th1 cytokine interferon-gamma. In addition, we have obtained evidence that ADO enhances IL-10 and decreases IL-12 production by immunostimulated macrophages. Thus, we will investigate the hypothesis that high extracellular concentrations of ADO may contribute to the deleterious immune hyporesponsiveness observed in patients with CARS. Because ADO exerts its biological effects by binding to any of 4 specific cell surface receptors, we also hypothesize that ADO shifts the immune response from a proinflammatory to an anti-inflammatory one through the activation of certain ADO receptors present on T cells and macrophages. We will test these hypotheses both in vitro using T cell and macrophage systems as well as in vivo using the mouse cecal ligation and puncture model of MOF.
| Haskó, György; Antonioli, Luca; Cronstein, Bruce N (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307-313 |
| Csóka, Balázs; Németh, Zoltán H; Szabó, Ildikó et al. (2018) Macrophage P2X4 receptors augment bacterial killing and protect against sepsis. JCI Insight 3: |
| Antonioli, Luca; Blandizzi, Corrado; Pacher, Pál et al. (2018) Quorum sensing in the immune system. Nat Rev Immunol 18:537-538 |
| Csóka, Balázs; Németh, Zoltán H; Duerr, Claudia U et al. (2018) Adenosine receptors differentially regulate type 2 cytokine production by IL-33-activated bone marrow cells, ILC2s, and macrophages. FASEB J 32:829-837 |
| Csóka, Balázs; Tör?, Gábor; Vindeirinho, Joana et al. (2017) A2A adenosine receptors control pancreatic dysfunction in high-fat-diet-induced obesity. FASEB J 31:4985-4997 |
| Antonioli, Luca; Yegutkin, Gennady G; Pacher, Pál et al. (2016) Anti-CD73 in cancer immunotherapy: awakening new opportunities. Trends Cancer 2:95-109 |
| Csóka, Balázs; Németh, Zoltán H; Tör?, Gábor et al. (2015) Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing. FASEB J 29:3626-37 |
| Antonioli, Luca; Blandizzi, Corrado; Csóka, Balázs et al. (2015) Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations. Nat Rev Endocrinol 11:228-41 |
| Csóka, Balázs; Németh, Zoltán H; Tör?, Gábor et al. (2015) CD39 improves survival in microbial sepsis by attenuating systemic inflammation. FASEB J 29:25-36 |
| Antonioli, Luca; Haskó, György; Fornai, Matteo et al. (2014) Adenosine pathway and cancer: where do we go from here? Expert Opin Ther Targets 18:973-7 |
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