Abstract
Adenosine, prostaglandin E2, or increased intracellular cyclic AMP concentration each elicit potent anti-inflammatory events in human neutrophils by inhibiting functions such as phagocytosis, superoxide production, adhesion and cytokine release. However, the endogenous molecular pathways mediating these actions are poorly understood. In the present study, we examined their impact on the gene expression profile of stimulated neutrophils. Purified blood neutrophils from healthy donors were stimulated with a cocktail of inflammatory agonists in the presence of at least one of the following anti-inflammatory agents: adenosine A2A receptor agonist CGS 21680, prostaglandin E2, cyclic-AMP-elevating compounds forskolin and RO 20-1724. Total RNA was analyzed using gene chips and real-time PCR. Genes encoding transcription factors, enzymes and regulatory proteins, as well as secreted cytokines/chemokines showed differential expression. We identified 15 genes for which the anti-inflammatory agents altered mRNA levels. The agents affected the expression profile in remarkably similar fashion, suggesting a central mechanism limiting cell activation. We have identified a set of genes that may be part of important resolution pathways that interfere with cell activation. Identification of these pathways will improve understanding of the capacity of tissues to terminate inflammatory responses and contribute to the development of therapeutic strategies based on endogenous resolution.
Highlights
Neutrophils constitute the majority of circulating leukocytes and are often the first cells to migrate toward inflammatory lesions, where they exert host defense functions including the phagocytosis of cell debris and invading microorganisms, the generation of oxygen-derived reactive agents and the release of proteolytic enzymes [1]
The scope of this work encompasses the development of novel therapeutic strategies based on enabling endogenous anti-inflammatory pathways in the treatment of inflammatory conditions such as rheumatoid arthritis, in which unchecked activation of cells can cause significant tissue damage
Cells responded to these different anti-inflammatory signals in a strikingly similar fashion, which suggests the engagement of a central endogenous system responsible for uncoupling selected neutrophil inflammatory functions
Summary
Neutrophils constitute the majority of circulating leukocytes and are often the first cells to migrate toward inflammatory lesions, where they exert host defense functions including the phagocytosis of cell debris and invading microorganisms, the generation of oxygen-derived reactive agents and the release of proteolytic enzymes [1]. Endogenous adenosine and A2AR agonists have shown to be potent inhibitors of leukotriene and platelet-activating factor synthesis [13,18,19,20] and in contrast, to stimulate COX-2 expression in neutrophils [21,22], increasing the capacity of these cells to produce prostaglandin E2. This shift in the profile of lipid mediator production from leukotrienes to prostaglandin E2 may contribute to preventing subsequent neutrophil-elicited inflammatory events. The gene activities that control inflammation resolution pathways remain poorly understood
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