Regulation of adenosine receptor subtypes during cultivation of human monocytes: role of receptors in preventing lipopolysaccharide-triggered respiratory burst (original) (raw)
Related papers
2001
Adenosine is a signaling nucleoside that is elevated in the lungs of asthmatics. We have engineered a mouse model that has elevated levels of adenosine as a result of the partial expression of the enzyme that metabolizes adenosine, adenosine deaminase (ADA). Mice with lowered levels of ADA enzymatic activity were generated by the ectopic expression of an ADA minigene in the gastrointestinal tract of otherwise ADA-deficient mice. These mice developed progressive lung inflammation and damage and died at 4-5 mo of age from respiratory distress. Associated with this phenotype was a progressive increase in lung adenosine levels. Examination of airway physiology at 6 wk of age revealed alterations in airway hyperresponsiveness. This was reversed following the lowering of adenosine levels using ADA enzyme therapy and also through the use of the adenosine receptor antagonist theophylline, implicating both the nucleoside and its receptors in airway physiological alterations. All four adenosine receptors were expressed in the lungs of both control and partially ADA-deficient mice. However, transcript levels for the A 1 , A 2B , and A 3 adenosine receptors were significantly elevated in partially ADA-deficient lungs. There was a significant increase in alveolar macrophages, and monocyte chemoattractant protein-3 was found to be elevated in the bronchial epithelium of these mice, which may have important implications in the regulation of pulmonary inflammation and airway hyperresponsiveness. Collectively, these findings suggest that elevations in adenosine can directly impact lung inflammation and physiology.
The Journal of …, 2001
Adenosine is a signaling nucleoside that is elevated in the lungs of asthmatics. We have engineered a mouse model that has elevated levels of adenosine as a result of the partial expression of the enzyme that metabolizes adenosine, adenosine deaminase (ADA). Mice with lowered levels of ADA enzymatic activity were generated by the ectopic expression of an ADA minigene in the gastrointestinal tract of otherwise ADA-deficient mice. These mice developed progressive lung inflammation and damage and died at 4-5 mo of age from respiratory distress. Associated with this phenotype was a progressive increase in lung adenosine levels. Examination of airway physiology at 6 wk of age revealed alterations in airway hyperresponsiveness. This was reversed following the lowering of adenosine levels using ADA enzyme therapy and also through the use of the adenosine receptor antagonist theophylline, implicating both the nucleoside and its receptors in airway physiological alterations. All four adenosine receptors were expressed in the lungs of both control and partially ADA-deficient mice. However, transcript levels for the A 1 , A 2B , and A 3 adenosine receptors were significantly elevated in partially ADA-deficient lungs. There was a significant increase in alveolar macrophages, and monocyte chemoattractant protein-3 was found to be elevated in the bronchial epithelium of these mice, which may have important implications in the regulation of pulmonary inflammation and airway hyperresponsiveness. Collectively, these findings suggest that elevations in adenosine can directly impact lung inflammation and physiology.
Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury
Journal of Clinical Investigation, 2006
Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A 2B adenosine receptor (A 2B AR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A 2B AR in vivo, ADA-deficient mice were treated with the selective A 2B AR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and vehicle-treated ADAdeficient mice developed pulmonary inflammation, fibrosis, and enlargement of alveolar airspaces; conversely,
Expression of adenosine receptors in monocytes from patients with bronchial asthma
Biochemical and Biophysical Research Communications, 2015
Adenosine is generated from adenosine triphosphate, which is released by stressed and damaged cells. Adenosine levels are significantly increased in patients with bronchial asthma (BA) and mediate mast cell degranulation and bronchoconstriction. Over the last decade, increasing evidence has shown that adenosine can modulate the innate immune response during monocytes differentiation towards mature myeloid cells. These adenosine-differentiated myeloid cells, characterized by co-expression of monocytes/macrophages and dendritic cell markers such as CD14 and CD209, produce high levels of pro-inflammatory cytokines, thus contributing to the pathogenesis of BA and chronic obstructive pulmonary disease. We found that expression of ADORA2A and ADORA2B are increased in monocytes obtained from patients with BA, and are associated with the generation of CD14(pos)CD209(pos) pro-inflammatory cells. A positive correlation between expression of ADORA2B and IL-6 was identified in human monocytes and may explain the increased expression of IL-6 mRNA in asthmatics. Taken together, our results suggest that monocyte-specific expression of A2 adenosine receptors plays an important role in pro-inflammatory activation of human monocytes, thus contributing to the progression of asthma.
Annals of the New York Academy of Sciences, 1985
Neutrophils are the most abundant circulating white blood cells and constitute the first l i e of defense by the host against invading organisms. Neutrophils may also mediate tissue injury in inflammatory reactions of less certain origin, such as rheumatoid arthritis. Upon stimulation in vitro with soluble agents such as the surrogate bacterial chemoattractant N-formyl-methionyl-leucyl-phenylalanine (FMLP), the activated complement component C5a in zymosan-treated serum, the lectin concanavalin A, and the calcium ionophore A23 187, neutrophils generate toxic oxygen metabolites, such as superoxide anion (02-), degranulate or release their lysosomal enzymes and aggregate. This process has been termed stimulus-response coupling in the neutrophil.' We have recently demonstrated that adenosine inhibits the ability of neutrophils to generate superoxide anion? Further, we have shown that inhibition of superoxide anion generation by adenosine is mediated by a specific receptor present on the surface of neutrophils. In addition, we have characterized the adenosine receptor on human neutrophils as an adenosine A, receptor. The physiologic effects of adenosine were first noted 50 years ago by Drury and Szent-Gyorgyi,' but it was not until the 1970s that the mechanism by which adenosine effected these physiologic changes was elucidated. In 1970 Sattin and Rall demonstrated that adenosine was a potent neurotransmitter that acts extracellularly via effects on intracellular CAMP." Subsequent studies of the neurotransmitter and hormonal properties of adenosine have shown that adenosine acts via stimulation of specific receptors that effect changes in intracellular CAMP concentrations? aThis work was supported by grant no.
ChemMedChem, 2008
Adenosine is a key endogenous molecule that regulates tissue function by activating four G-proteincoupled adenosine receptors: A 1 , A 2A , A 2B and A 3. Cells of the immune system express these receptors and are responsive to the modulatory effects of adenosine in an inflammatory environment. Animal models of asthma, ischaemia, arthritis, sepsis, inflammatory bowel disease and wound healing have helped to elucidate the regulatory roles of the various adenosine receptors in dictating the development and progression of disease. This recent heightened awareness of the role of adenosine in the control of immune and inflammatory systems has generated excitement regarding the potential use of adenosine-receptor-based therapies in the treatment of infection, autoimmunity, ischaemia and degenerative diseases.