Glucocorticoids promote survival of anti-inflammatory macrophages via stimulation of adenosine receptor A3.
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.
Barczyk
Katarzyna
K
Institute of Immunology, University of Muenster, Muenster, Germany.
Ehrchen
Jan
J
Tenbrock
Klaus
K
Ahlmann
Martina
M
Kneidl
Jessica
J
Viemann
Dorothee
D
Roth
Johannes
J
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008775:Methylprednisolone / Q000494:pharmacology; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014221:Triamcinolone / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D017931:DNA Primers; D005938:Glucocorticoids; D043684:Receptor, Adenosine A3; D014221:Triamcinolone; D003907:Dexamethasone; D020169:Caspases; D019311:Staurosporine; D008775:Methylprednisolone