Inhibition of human monocyte TNF production by adenosine receptor agonists

Vraux, Valérie Le; Chen, Y.L.; Masson, Isabelle; Sousa, Martine De; Giroud, Jean‐Paul; Florentin, I.; Chauvelot‐Moachon, Laurence

doi:10.1016/0024-3205(93)90632-d

Cited by 110 publications

(43 citation statements)

References 30 publications

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“…Moreover, it has been firmly established that the increased adenosine secretion and activation of its receptors inhibit the production of many proinflammatory cytokines, including IL-12, TNF-␣, and other inflammatory mediators (19,(35)(36)(37)(38). It is likely then that at inflamed sites, where proinflammatory cytokines such as IL-1 and TNF-␣ are abundantly secreted, mostly by monocytes/macrophages, the subsequent up-regulation of A 2A and A 2B receptors on endothelial cells and other inflammatory cells along with endogenous adenosine release constitutes a feedback loop to suppress further inflammation.…”

Section: Discussionmentioning

confidence: 99%

Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells

Khoa

Williams

Kelly

et al. 2003

The Journal of Immunology

118

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We and others have shown that adenosine, acting at its receptors, is a potent modulator of inflammation and angiogenesis. To better understand the regulation of adenosine receptors during these processes we studied the effects of IL-1, TNF-α, and IFN-γ on expression and function of adenosine receptors and select members of their coupling G proteins in human dermal microvascular endothelial cells (HMVEC). HMVEC expressed message and protein for A2A and A2B, but not A1 or A3 receptors. IL-1 and TNF-α treatment increased message and protein expression of A2A and A2B receptor. IFN-γ treatment also increased the expression of A2B receptors, but decreased expression of A2A receptors. Resting HMVEC and IFN-γ-treated cells showed minimal cAMP response to the selective A2A receptor agonist 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094). In contrast, MRE0094 stimulated a dose-dependent increase in cAMP levels in TNF-α-treated cells that was almost completely blocked by the A2A receptor antagonist ZM-241385 (4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol). The nonselective adenosine receptor agonist 5′-(N-ethylcarboxamido)adenosine increased cAMP levels in both TNF-α- and IFN-γ-treated cells, but not control cells, and its effect was only partially reversed by ZM-241385 in TNF-α-treated cells and not affected in IFN-γ-treated cells. HMVEC expressed a higher level of G protein β1 isoform than β4 isoform. Although none of the cytokines tested affected Gβ1 expression, both IL-1 and TNF-α significantly up-regulated Gβ4 expression. These findings indicate that inflammatory cytokines modulate adenosine receptor expression and function on HMVECs and suggest that the interaction between proinflammatory cytokines and adenosine receptors may affect therapeutic responses to anti-inflammatory drugs that act via adenosine-dependent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells

Khoa

Williams

Kelly

et al. 2003

The Journal of Immunology

118

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“…3 A and B). The TNF-␣-suppressive activity of steroids is well documented (26)(27)(28) and it has been noted that dipyridamole exhibits TNF-␣ suppressive effects, possibly through potentiation of adenosine-mediated action at the adenosine A2a receptor (29)(30)(31)(32). However, their combined action in vitro has not been described, nor would knowledge of their proposed modes of action have predicted that in combination they would yield the observed interaction effect (Fig.…”

Section: Chtsmentioning

confidence: 99%

Systematic discovery of multicomponent therapeutics

Borisy

Elliott

Hurst

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

549

522

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Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of Ϸ120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-␣ in human primary peripheral blood mononuclear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.M odern biological research and much of drug discovery is often driven by the search for new molecularly targeted therapeutics (1-3). In this approach, a specific protein is studied in vitro, in cells and in whole organisms, and evaluated as a drug target for a specific therapeutic indication (3, 4). The refinement of this approach has resulted in the ability to discover compounds with great selectivity for a chosen protein target. The recent success of Gleevec (imatinib mesylate), an inhibitor of the breakpoint cluster regionabelson (BCR-ABL) kinase, and of selective cyclooxygenase-2 (COX-2) inhibitors Vioxx (rofecoxib) and Celebrex (celecoxib) are evidence that the target-based approach can be successful (5, 6).Systems biology, however, has revealed that human cells and tissues are composed of complex, networked systems with redundant, convergent and divergent signaling pathways (7-10). For example, the redundant function of proteins involved in cell-cycle regulation (11) has inspired efforts to intervene simultaneously at multiple points in these signaling pathways (12). A drug discovery approach consonant with this systems biology framework, and complementary to the target-based approach, entails identification of combinations of small molecules that perturb cellular signaling networks in a desired fashion.Recognition of the potential for multipoint intervention in biology and medicine has a long history. As early as 1928, Loewe (13) observed and quantified effects of combinations of compounds that were different from, and not predicted by, the activities of the constituents. The conc...

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“…Because TNF-α was one of the first cytokines to be discovered, there is a plethora of information available on the regulation of TNF-α production by adenosine receptors. Vraux et al, 1993) adenosine receptor agonists were shown to suppress TNF-α production by LPS (TLR4 ligand)-challenged human monocytes with the following rank order of potency: NECA>R-PIA=CGS 21680>2-CADO (2-chloroadenosine)=CHA (N 6 -cyclohexyladenosine). Because NECA was the most potent agonist, a role for the A 2B receptor can be considered, because if NECA is the most potent agonist in a system, it indicates a predominant role for A 2B receptors (Feoktistov & Biaggioni, 1997).…”

Section: Adenosine Suppresses Tnf-α Production By Monocytes and Macromentioning

confidence: 99%

Shaping of monocyte and macrophage function by adenosine receptors

Haskó

Pacher

Deitch

et al. 2007

Pharmacology & Therapeutics

194

154

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Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-α, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

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Inhibition of human monocyte TNF production by adenosine receptor agonists

Cited by 110 publications

References 30 publications

Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells

Th1 Cytokines Regulate Adenosine Receptors and Their Downstream Signaling Elements in Human Microvascular Endothelial Cells

Systematic discovery of multicomponent therapeutics

Shaping of monocyte and macrophage function by adenosine receptors

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