Acute adrenergic stress inhibits proliferation of murine hematopoietic progenitor cells via p38/MAPK signaling.
Acute adrenergic stress is a cause of hematopoietic failure that accompanies severe injury. Although the communication between neuronal and immune system is well documented and catecholamines are known as important regulators of homeostasis, the molecular mechanisms of hematopoietic failure are not well understood. To study the influence of adrenergic stress on hematopoietic progenitor cells (HPCs), which recently have been found to express adrenergic receptors, Lin(-),Sca(+), cells were isolated and treated with alpha- and beta-adrenergic agonists in vitro. Indeed, this stimulation resulted in significantly decreased colony formation capacity using granulocyte/macrophage colony-forming unit assays. This decline was dependent on the formation of reactive oxygen species (ROS) and activation of the p38/mitogen-activated protein kinase (MAPK) pathway, since the addition of antioxidants or a p38 inhibitor restored CFU formation. DNA damage by adrenergically induced ROS, however, does not seem to account for the reduction of colonies. Thus, catecholamine/p38/MAPK is identified as a key signal transduction pathway in HPCs besides those dependent on Wnt, Notch, and sonic hedgehog. Furthermore, a well-known target of p38 signaling, p16 is transcriptionally activated after adrenergic stimulation, suggesting that cell cycle arrest might importantly contribute to hematopoietic failure and immune dysfunctions after severe injury. Since increased levels of catecholamines are also observed in other conditions, such as during aging which is linked with decline of immune functions, adrenergic stress might as well contribute to the lowered immune defence in the elderly.
Schraml
Elisabeth
E
Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University of Graz, Graz, Austria. elisabeth.schraml@boku.ac.at
Fuchs
Robert
R
Kotzbeck
Petra
P
Grillari
Johannes
J
Schauenstein
Konrad
K
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000067696:Ataxin-1; D000067528:Ataxins; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C000593749:ATXN1 protein, human; D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases