Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α

McWhinney, Charlene D.; Dudley, Mark W.; Bowlin, Terry L.; Peet, Norton P.; Schook, Lawrence B.; Bradshaw, Marite; De, Mamata; Borcherding, David R.; Edwards, Carl K.

doi:10.1016/0014-2999(96)00272-5

Cited by 116 publications

(68 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…31), although the A 2A receptor is considered to be the most important endogenous regulator of acute inflammation (13). In murine macrophages, A 2A , A 2B , and A 3 receptors have all been reported to diminish inflammatory cytokine secretion by macrophages (32)(33)(34)(35)(36)(37), although in human macrophages, the A 2A receptor appears to be the dominant regulator of cytokine secretion (38,39). The differences in adenosine receptor predominance observed in these studies may have resulted from the different sources of macrophages studied (bone marrow, peripheral blood, peritoneum) or from altered adenosine receptor expression in monocyte/macrophages after release from the bone marrow (40) or following stimulation with various cytokines.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Montesinos¹,

Desai²,

Delano³

et al. 2003

Arthritis & Rheumatism

189

116

View full text Add to dashboard Cite

Objective. Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor ( Results. Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor ␣ accumulation in the exudates of wildtype mice, but not in those of A 2A or A 3 receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A 2A knockout, A 3 knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68.Conclusion. These findings confirm that adenosine, acting at A 2A and A 3 receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.Low-dose weekly methotrexate is the "gold standard" of therapy in rheumatoid arthritis and other inflammatory diseases. Methotrexate's mechanism of action in the treatment of inflammatory diseases has been the subject of some controversy, although in previous studies, investigators in our group have demonstrated that adenosine mediates the antiinflammatory effects of methotrexate treatment in models of acute and chronic inflammation (1,2). Adenosine, whether released from injured cells or tissues or applied exogenously, regulates inflammation via interaction with one or more of the 4 known receptors for adenosine (A 1 , A 2A , A 2B , and A 3 ), as demonstrated by many in vitro and in vivo pharmacologic studies (for review, see ref.3). The demonstration that adenosine mediates the antiinflammatory effects of methotrexate in in vivo models of acute inflammation rests upon reversal of the antiinflammatory effects of methotrexate, either by enzymatic hydrolysis of adenosine by adenosine deaminase or by administration of adenosine receptor antagonists to reverse the antiinflammatory effects of methotrexate treatment (1,2). Although the antiinflammatory effects of methotrexate are mediated by multiple adenosine receptors in the adjuvant arthritis model of inflammation (2), the identity of the receptor(s) involved in the suppression of inflammation in models of acute inflammation has not been so well characterized.

show abstract

Section: Discussionmentioning

confidence: 99%

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Montesinos¹,

Desai²,

Delano³

et al. 2003

Arthritis & Rheumatism

189

116

View full text Add to dashboard Cite

show abstract

“…To study the regulation of IL-10 production by adenosine, we used RAW 264.7 macrophages; these cells have been shown to express adenosine receptors (20,27,28,33), and many aspects of the regulation of IL-10 gene expression have been uncovered using this cell line (6,7,13). RAW 264.7 macrophages produce constitutively low levels of IL-10.…”

Section: Adenosine Receptor Agonists Up-regulate Il-10 Production By mentioning

confidence: 99%

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Németh¹,

Lutz²,

Csóka³

et al. 2005

The Journal of Immunology

244

161

View full text Add to dashboard Cite

Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A1, A2A, A2B, and A3. Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3′-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3′-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3′-UTR of TNF-α mRNA. The IL-10 3′-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3′-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A2B receptor, because the order of potency of selective agonists was 5′-N-ethylcarboxamidoadenosine (NECA) > N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) > 2-chloro-N6-cyclopentyladenosine (CCPA) = 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.

show abstract

“…Adenosine is known to bind to three different types of G-protein coupled cell surface receptors, called the A1, A2, and A3 adenosine receptors. Monocyte and macrophages are known to express A1 and A2 receptors, while A3 receptors are expressed on mast cells (for references see McWhinney et al, 1996;Hasko et al, 2000a, b). By using specific receptor anatagonists, we found that the effect of adenosine on TNF-induced NF-kB in myeloid cells is mediated through A 2 -type but not A 1 -type receptors.…”

Section: Adenosine Blocks Tnf-mediated Nf-jb Activation S Majumdar Anmentioning

confidence: 99%

“…This purine nucleoside ameliorates the fate of a variety of immune-mediated diseases such as pleural inflammation (Schrier et al, 1990), ischemia-reperfusion injury (Janier et al, 1993;Bouma et al, 1997), brain ischemia and trauma (Marangos et al, 1990), rheumatoid arthritis (RA) (Green et al, 1991;Szabo et al, 1998), and endotoxin-mediated shock (Parmely et al, 1993;Hasko et al, 1996). Several of these effects could be explained by the ability of adenosine to suppress TNF produced by activated macrophages and Kupffer cells (Bouma et al, 1994;Reinstein et al, 1994;McWhinney et al, 1996;Bowlin et al, 1997;Hasko et al, 2000a) and to suppress expression of adhesion molecules by activated human endothelial cells (Bouma et al, 1996). Indeed, suppression of lipopolysaccharide (LPS)-induced TNF production by adenosine has been demonstrated in human cardiac tissue (Wagner et al, 1998a, b).…”

Section: Introductionmentioning

confidence: 99%

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

Majumdar

Aggarwal

2003

Oncogene

View full text Add to dashboard Cite

Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α

Cited by 116 publications

References 37 publications

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

Contact Info

Product

Resources

About

Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α

Cited by 116 publications

References 37 publications

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine Augments IL-10 Production by Macrophages through an A2B Receptor-Mediated Posttranscriptional Mechanism

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

Contact Info

Product

Resources

About

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68

Adenosine A_2A or A₃ receptors are required for inhibition of inflammation by methotrexate and its analog MX‐68