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Cutting Edge |
* Section of Hematology-Oncology, Department of Medicine, University of Illinois and West Side Veterans Administration Medical Center, Chicago, IL 60607; and
Section of Hematology-Oncology, University of Chicago, Chicago, IL 60637
Myelosuppressive cytokines, in particular
IFN-
and TNF-
, 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- and TNF- 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- and TNF- 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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