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The Journal of Immunology, 2002, 168: 5984-5988.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Activation of the p38 Mitogen-Activated Protein Kinase Signaling Pathway Mediates Cytokine-Induced Hemopoietic Suppression in Aplastic Anemia1

Amit Verma*, Dilip K. Deb*, Antonella Sassano*, Suman Kambhampati*, Amittha Wickrema*,{dagger}, Shahab Uddin*, Mani Mohindru*, Koen Van Besien* and Leonidas C. Platanias2,*

* Section of Hematology-Oncology, Department of Medicine, University of Illinois and West Side Veterans Administration Medical Center, Chicago, IL 60607; and {dagger} Section of Hematology-Oncology, University of Chicago, Chicago, IL 60637

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.




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