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Differential regulatory effects of adenosine on cytokine release by activated human monocytes
M G Bouma1, R K Stad, F A van den Wildenberg
1Department of Surgery, University of Limburg, Maastricht, The Netherlands.
Abstract:
Adenosine is an endogenous nucleoside that can modulate the function of cells involved in the inflammatory response, such as polymorphonuclear leukocytes (PMN) and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the pathogenesis of ischemia-reperfusion injury, a pathologic phenomenon that is associated with excessive ATP catabolism and subsequent local release of adenosine. The "retaliatory" metabolite adenosine has been shown to interfere with PMN function, thereby attenuating the deleterious consequences of ischemia and reperfusion. In this study, we demonstrate that adenosine inhibits the production of TNF-alpha, IL-6, and IL-8 by LPS-activated human monocytes with a differential potency. The A2 receptor-specific adenosine analogues 2-chloroadenosine and 5'-N-ethylcarboxamidoadenosine (NECA) were most effective in attenuating LPS-induced cytokine production, whereas the A1-selective adenosine analogue N6-cyclopentyladenosine (CPA) was less effective, indicating that inhibition of cytokine production by adenosine is primarily an A2 receptor-mediated event. The observed inhibitory effects were not restricted to endotoxin-induced cytokine production, because adenosine also inhibited TNF-alpha production by monocytes stimulated with the proinflammatory cytokine IL-1 beta. Again, 2-chloroadenosine and NECA reduced IL-beta-induced TNF-alpha production more potently than CPA. In contrast, adenosine enhanced production of IL-6 and IL-8 by monocytes stimulated with IL-1 beta. Furthermore, only 2-chloroadenosine, but not NECA, strongly inhibited cytokine-induced IL-6 and IL-8 production. These results suggest an additional A2 receptor-mediated mechanism of retaliatory action of adenosine under pathologic conditions where cytokine production by activated mononuclear phagocytes is involved, such as ischemia-reperfusion injury and septic shock.
Insights
Adenosine, particularly via A2 receptors, inhibits inflammatory cytokine production by monocytes during conditions like ischemia-reperfusion injury. This suggests a protective role for adenosine in inflammatory diseases.
Area of Science:
- Immunology
- Pharmacology
- Pathophysiology
Background:
- Adenosine is an endogenous nucleoside modulating inflammatory cell function.
- Cytokine release by mononuclear phagocytes contributes to ischemia-reperfusion injury.
- Adenosine acts as a
- retaliatory
Purpose of the Study:
- To investigate adenosine's effect on cytokine production by LPS-activated human monocytes.
- To determine the receptor subtypes involved in adenosine's immunomodulatory actions.
- To explore adenosine's role in inflammatory conditions like ischemia-reperfusion injury and septic shock.
Main Methods:
- Utilized human monocytes activated with lipopolysaccharide (LPS) or IL-1 beta.
- Administered adenosine and its receptor-specific analogues (A1 and A2 selective).
- Quantified the production of key cytokines: TNF-alpha, IL-6, and IL-8.
Main Results:
- Adenosine significantly inhibited LPS-induced TNF-alpha, IL-6, and IL-8 production.
- A2 receptor agonists (2-chloroadenosine, NECA) were more potent inhibitors than A1 agonists (CPA).
- Adenosine differentially affected IL-1 beta-induced cytokine production, inhibiting TNF-alpha but enhancing IL-6 and IL-8.
Conclusions:
- Adenosine's inhibition of pro-inflammatory cytokine production is primarily mediated via A2 receptors.
- Adenosine exhibits a complex, context-dependent immunomodulatory role.
- These findings highlight adenosine's potential therapeutic relevance in inflammatory diseases involving mononuclear phagocytes.