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

Majumdar, S.; Aggarwal, Bharat B.

doi:10.1038/sj.onc.1206184

Cited by 95 publications

(89 citation statements)

References 51 publications

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“…A comprehensive analysis of multiple intracellular signaling mechanisms found that the decrease in TNF-α production after I-ABA exposure was associated with changes in activation of the activator protein-1 (AP-1) transcription factor system, whereas the activity of I-ABA was independent of mitogen-activated protein (MAP) kinases and nuclear factor-κB (NF-κB), as well as PKA, PKC, and PLC. The inability of adenosine, at least at physiological concentrations, to attenuate LPS-induced NF-κB activation was confirmed by other studies (Majumdar & Aggarwal, 2003;Nemeth et al, 2003;Pinhal-Enfield et al, 2003).…”

Section: Human Monocytes/macrophages-in Initial Studies (Lesupporting

confidence: 67%

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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Section: Human Monocytes/macrophages-in Initial Studies (Lesupporting

confidence: 67%

Shaping of monocyte and macrophage function by adenosine receptors

Haskó

Pacher

Deitch

et al. 2007

Pharmacology & Therapeutics

194

154

View full text Add to dashboard Cite

show abstract

“…Extracellular adenosine is also an important inhibitor of T-cell functions. Similar to its effect on B cells, adenosine inhibits T-cell receptorinduced NF-kB activation (Majumdar and Aggarwal, 2003). The A2A receptor dominantly regulates T-cell functions and is significantly upregulated upon T-cell activation.…”

Section: Adenosine-mediated Immunosuppressionmentioning

confidence: 90%

Extracellular adenosine triphosphate and adenosine in cancer

2010

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Adenosine triphosphate (ATP) is actively released in the extracellular environment in response to tissue damage and cellular stress. Through the activation of P2X and P2Y receptors, extracellular ATP enhances tissue repair, promotes the recruitment of immune phagocytes and dendritic cells, and acts as a co-activator of NLR family, pyrin domain-containing 3 (NLRP3) inflammasomes. The conversion of extracellular ATP to adenosine, in contrast, essentially through the enzymatic activity of the ecto-nucleotidases CD39 and CD73, acts as a negativefeedback mechanism to prevent excessive immune responses. Here we review the effects of extracellular ATP and adenosine on tumorigenesis. First, we summarize the functions of extracellular ATP and adenosine in the context of tumor immunity. Second, we present an overview of the immunosuppressive and pro-angiogenic effects of extracellular adenosine. Third, we present experimental evidence that extracellular ATP and adenosine receptors are expressed by tumor cells and enhance tumor growth. Finally, we discuss recent studies, including our own work, which suggest that therapeutic approaches that promote ATP-mediated activation of inflammasomes, or inhibit the accumulation of tumorderived extracellular adenosine, may constitute effective new means to induce anticancer activity.

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“…Therefore, ADORA2A binding likely inhibits a common proinflammatory activator (11,26). Multiple mechanisms surely exist, but fundamental to the antiinflammatory effects of the ADORA2A pathway is its inhibition of the transcription factor NF-kB (50,51). CGS-21680, a specific ADORA2A agonist, blocked 50% of the oxygen-induced increase in NF-kB activity in macrophages exposed to LPS.…”

Section: Discussionmentioning

confidence: 99%

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

Aggarwal¹,

D’Alessio²,

Eto³

et al. 2013

Am J Respir Cell Mol Biol

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Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality. Exacerbating factors increasing the risk of ARDS remain unknown. Supplemental oxygen is often necessary in both mild and severe lung disease. The potential effects of supplemental oxygen may include augmentation of lung inflammation by inhibiting antiinflammatory pathways in alveolar macrophages. We sought to determine oxygen-derived effects on the anti-inflammatory A2A adenosinergic (ADORA2A) receptor in macrophages, and the role of the ADORA2A receptor in lung injury. Wild-type (WT) and ADORA2A2/2 mice received intratracheal lipopolysaccharide (IT LPS), followed 12 hours later by continuous exposure to 21% oxygen (control mice) or 60% oxygen for 1 to 3 days. We measured the phenotypic endpoints of lung injury and the alveolar macrophage inflammatory state. We tested an ADORA2A-specific agonist, CGS-21680 hydrochloride, in LPS plus oxygen-exposed WT and ADORA2A 2/2 mice. We determined the specific effects of myeloid ADORA2A, using chimera experiments. Compared with WT mice, ADORA2A2/2 mice exposed to IT LPS and 60% oxygen demonstrated significantly more histologic lung injury, alveolar neutrophils, and protein. Macrophages from ADORA2A 2/2 mice exposed to LPS plus oxygen expressed higher concentrations of proinflammatory cytokines and cosignaling molecules. CGS-21680 prevented the oxygen-induced augmentation of lung injury after LPS only in WT mice. Chimera experiments demonstrated that the transfer of WT but not ADORA2A 2/2 bone marrow cells into irradiated ADORA2A2/2 mice reduced lung injury after LPS plus oxygen, demonstrating myeloid ADORA2A protection. ADORA2A is protective against lung injury after LPS and oxygen. Oxygen after LPS increases macrophage activation to augment lung injury by inhibiting the ADORA2A pathway.

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

Cited by 95 publications

References 51 publications

Shaping of monocyte and macrophage function by adenosine receptors

Shaping of monocyte and macrophage function by adenosine receptors

Extracellular adenosine triphosphate and adenosine in cancer

Macrophage A2A Adenosinergic Receptor Modulates Oxygen-Induced Augmentation of Murine Lung Injury

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