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, 116 (3), 446-55

Glucocorticoids Promote Survival of Anti-Inflammatory Macrophages via Stimulation of Adenosine Receptor A3

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Glucocorticoids Promote Survival of Anti-Inflammatory Macrophages via Stimulation of Adenosine Receptor A3

Katarzyna Barczyk et al. Blood.

Abstract

Active resolution of inflammation is a previously unrecognized process essential for tissue homeostasis. Monocytes play a pivotal role in the generation as well as resolution of inflammation. Glucocorticoids (GCs) are widely used anti-inflammatory agents. We demonstrate that GCs exhibit antiapoptotic effects in monocytes resulting in differentiation to an anti-inflammatory phenotype. The molecular basis of this novel antiapoptotic effect is a prolonged activation of the extracellular signal regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway resulting in inhibition of caspase activities and expression of antiapoptotic genes via activation of c-Myc. We identified up-regulation and activation of A3 adenosine receptor (A3AR) as the initial trigger of this antiapoptotic pathway. In summary, we deciphered a novel molecular pathway promoting survival of anti-inflammatory monocytes. Specific activation of A3AR or its downstream signaling pathways may thus be a novel strategy to modulate inflammation in autoimmune disorders with fewer side effects via induction of inflammatory resolution rather than immunosuppression.

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