Cutting edge: activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia.
Myelosuppressive cytokines, in particular IFN-gamma and TNF-alpha, play an important role in the pathogenesis of idiopathic aplastic anemia in humans. It is unknown whether these negative regulators of hemopoiesis suppress stem cells by activating a common signaling cascade or via distinct nonoverlapping pathways. In this study, we provide evidence that a common element in signaling for IFN-gamma and TNF-alpha in human hemopoietic progenitors is the p38/MapKapK-2 signaling cascade. Our studies indicate that pharmacological inhibition of p38 reverses the suppressive effects of IFN-gamma and TNF-alpha on normal human bone marrow-derived erythroid and myeloid progenitors. Most importantly, inhibition of p38 strongly enhances hemopoietic progenitor colony formation from aplastic anemia bone marrows in vitro. Thus, p38 appears to play a critical role in the pathogenesis of aplastic anemia, suggesting that selective pharmacological inhibitors of this kinase may prove useful in the treatment of aplastic anemia and other cytokine-mediated bone marrow failure syndromes.
Verma
Amit
A
Section of Hematology-Oncology, Department of Medicine, University of Illinois and West Side Veterans Administration Medical Center, Chicago, IL 60607, USA.
Deb
Dilip K
DK
Sassano
Antonella
A
Kambhampati
Suman
S
Wickrema
Amittha
A
Uddin
Shahab
S
Mohindru
Mani
M
Van Besien
Koen
K
Platanias
Leonidas C
LC
D000741:Anemia, Aplastic / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2