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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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Myelosuppressive cytokines, particularly IFN-{gamma} and TNF-{alpha}, have been implicated in the pathogenesis of bone marrow failure syndromes in humans (1, 2, 3). It is well established that abnormally high levels of these cytokines are present in the bone marrow and peripheral blood of patients with aplastic anemia, and there is strong evidence that these cytokines mediate hemopoietic stem cell suppression (1, 2, 3, 4, 5, 6, 7, 8).

IFN-{gamma} and TNF-{alpha} are potent suppressors of normal hemopoiesis, and several studies have shown that these cytokines inhibit normal bone marrow colony formation for early (BFU-E)3 and late (CFU-E) erythroid progenitors, and for myeloid (CFU-GM) progenitors (9, 10, 11, 12). However, the specific signaling mechanisms by which these cytokines suppress human hemopoiesis are not known. It is unclear whether a common signaling cascade is used by the IFN-{gamma} and TNF-{alpha} receptors to mediate inhibition of hemopoietic progenitor cell growth or whether these cytokines suppress stem cells via activation of distinct cellular pathways.

In recent studies, we have shown that type I IFNs (IFN-{alpha} and IFN-{beta}) activate the p38 mitogen-activated protein (Map) kinase signaling cascade (13, 14, 15, 16). The IFN-{alpha}-dependent activation of p38 is required for transcriptional regulation of IFN-sensitive genes and is essential for the generation of the suppressive effects of IFN-{alpha} on the growth of chronic myelogenous leukemia progenitors (15), as well as normal eythroid and myeloid precursors (16). Interestingly, p38 is also required for the generation of the suppressive effects of TGF-{beta} on normal human progenitors (16), raising the possibility that this signaling cascade is acting as a common pathway in the human bone marrow, to mediate inhibitory signals for different myelosuppressive cytokines.

In this study, we sought to determine whether p38 is activated in response to TNF-{alpha} and/or IFN-{gamma} in primary human hemopoietic progenitors and, if so, whether its function is required for the induction of the suppressive effects of these cytokines. Our data demonstrate that IFN-{gamma} or TNF-{alpha} induce activation of p38 and its downstream effector MapKapK-2. In addition, concomitant treatment of human bone marrow cells with the p38-specific inhibitor SB203580 reverses the suppressive effects of IFN-{gamma} and/or TNF-{alpha} on hemopoietic cell progenitor growth. Most importantly, addition of this pharmacological inhibitor in aplastic anemia bone marrows increases hemopoietic progenitor colony formation, strongly suggesting that p38 plays a role in the pathogenesis of aplastic anemia.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cytokines and Abs

Human rIFN-{gamma} was provided by Hoffman LaRoche (Nutley, NJ). Human rTNF-{alpha} was obtained from R&D Systems (Minneapolis, MN). Abs against the phosphorylated/activated form of p38 and against p38 were obtained from New England Biolabs (Beverly, MA) and Santa Cruz Biotechnology (Santa Cruz, CA), respectively. An Ab against MapKapK-2 was obtained from Upstate Biotechnology. The pharmacological inhibitors SB203580, SB202474, and PD098059 were obtained from Calbiochem (La Jolla, CA).

Cell lysis, immunoblotting, and in vitro kinase assays

Human CD34+ cells were isolated from bone marrows or peripheral blood of normal healthy volunteers, after obtaining informed consent approved by the institutional review board of the University of Illinois. Progenitors at the CFU-E level of differentiation were enriched using the methodologies described in our previous studies (16, 17). Cell lysis, immunoblotting, and in vitro kinase assays were performed as in previous studies (13, 14, 15).

Hemopoietic progenitor cell assays

The effects of cytokines on hemopoietic cell progenitor colony formation were determined by clonogenic assays in methylcellulose, as in our previous studies (15, 16). Informed consent, approved by the institutional review board of the University of Illinois, was obtained by all participants in the study.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
We first examined whether IFN-{gamma} and/or TNF-{alpha} induce activation of the {alpha} and {beta} isoforms of p38 in CD34+ hemopoietic cells. To determine whether such activation occurs under physiologically relevant conditions, these studies were performed using enriched human CD34+ derived hemopoietic precursors (16, 17). The methodologies to enrich for normal human hemopoietic precursors have been described in our previous studies (16, 17). Enriched erythroid progenitors were incubated for different times in the presence or absence of TNF-{alpha} and/or IFN-{gamma}, and after cell lysis total lysates were resolved by SDS-PAGE and immunoblotted with an Ab against the phosphorylated/activated form of p38{alpha}. As shown in Fig. 1Go, treatment with TNF-{alpha} (Fig. 1Go, A and B) or IFN-{gamma} (Fig. 1Go, C and D) or the combination of both cytokines (Fig. 1Go, E and F) resulted in phosphorylation of the p38{alpha} isoform. Because there was no specific Ab available to detect the phosphorylated/activated form of the p38{beta} isoform, such an activation was examined by performing in vitro kinase assays on anti-p38{beta} immunoprecipitates from IFN-{gamma}- or TNF-{alpha}- treated cells. As shown in Fig. 2Go, IFN-{gamma}, TNF-{alpha}, or the combination of both cytokines resulted in p38{beta} activation, evidenced by the phosphorylation of activating transcription factor-2, used as an exogenous substrate (Fig. 2AGo and B). Thus, both IFN-{gamma} and TNF-{alpha} activate the {alpha} and {beta} isoforms of the p38 Map kinase in primary normal hemopoietic progenitors.



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  		FIGURE 1. TNF-{alpha}- and IFN-{gamma}-dependent activation of the p38{alpha} Map kinase in enriched primary human hemopoietic progenitors. Enriched erythroid progenitors at the CFU-E level of differentiation were incubated in the presence or absence of TNF-{alpha} (A and B) or IFN-{gamma} (C and D) for the indicated times. Equal amounts of total cell lysates were analyzed by SDS-PAGE and immunoblotted with an Ab against the phosphorylated/activated form of p38{alpha} (A and C). The blots were subsequently stripped and reprobed with an anti-p38{alpha} Ab, to control for protein loading (B and D). E, Enriched progenitors were preincubated with IFN-{gamma} for 60 min and were subsequently treated with TNF-{alpha} for the indicated times, in the continuous presence or absence of IFN-{gamma} as indicated. Equal amounts of total cell lysates were analyzed by SDS-PAGE and immunoblotted with an anti-phospho-p38{alpha} Ab. F, The blot shown in E was stripped and reprobed with an Ab against p38{alpha}, to control for protein loading.

 


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  		FIGURE 2. IFN-{gamma}- and TNF-{alpha}-dependent activation of the {beta} isoform of the p38 Map kinase and the MapKapK-2 kinase in enriched primary human hemopoietic progenitors. A, Enriched human progenitors were incubated with TNF-{alpha} or IFN-{gamma}, for 30 min at 37°C. Total lysates were immunoprecipitated with an anti-p38{beta} Ab, and immunoprecipitates (IP) were subjected to an in vitro kinase assay, using activating transcription factor-2 (ATF-2) as an exogenous substrate. Proteins were analyzed by SDS-PAGE, and phosphorylation was detected by autoradiography. B, The blot shown in A was probed with an Ab against p38{beta} to control for protein loading. C and D, Enriched human progenitors were incubated for 40 min in the presence or absence of TNF-{alpha} (C), IFN-{gamma} (D), or TNF-{alpha}, after preincubation for 60 min with IFN-{gamma}, in the presence or absence of Sb203580 as indicated (D). Cell lysates were immunoprecipitated with an anti-MapKapK-2 Ab, and proteins were subjected to an in vitro kinase assay, using Hsp-25 as an exogenous substrate. After SDS-PAGE analysis, phosphorylated proteins were detected by autoradiography. E, KG-1 cells were preincubated for 60 min in the presence or absence of SB203580 or SB202474, as indicated. The cells were subsequently treated with TNF-{alpha} for 30 min as indicated. Cell lysates were immunoprecipitated with an anti-MapKapK-2 Ab, and proteins were subjected to an in vitro kinase assay, using Hsp-25 as an exogenous substrate.

 
In previous studies, we have established that a downstream effector for p38 in human progenitors is the MapKapK-2 kinase (16). As our studies indicated that IFN-{gamma} and TNF-{alpha} activate p38 in primary hemopoietic progenitors, we determined whether this kinase is engaged downstream of p38 in primitive hemopoietic cells. Experiments were performed in which human progenitors were treated with IFN-{gamma}, TNF-{alpha}, or the combination of both cytokines, and the activation of MapKapK-2 was determined by immune complex kinase assays. Both IFN-{gamma} and TNF-{alpha} induced activation of MapKapK-2. Such activation was blocked by pretreatment of cells with the p38-specific inhibitor SB203580 (Fig. 2Go, C and D). In contrast, the structural analog SB202474 did not inhibit TNF-dependent MapKapK-2 activation in KG-1 cells, which are CD34+ (Fig. 2GoE), further indicating the specificity of the process.

We subsequently sought to obtain information on the role that the p38 Map kinase plays in cytokine-dependent suppression of normal hemopoietic progenitor cell growth. We performed experiments in which bone marrow mononuclear cells were cultured in methylcellulose with TNF-{alpha} or IFN-{gamma}, in the presence or absence of the p38-specific inhibitor SB203580, which blocks activation of both the p38{alpha} and p38{beta} isoforms. As expected, TNF-{alpha} or IFN-{gamma} inhibited colony formation for both myeloid (CFU-GM) and erythroid (BFU-E) progenitors (Fig. 3Go, A and B). Concomitant treatment of cells with SB203580 reversed the growth-inhibitory effects of either TNF-{alpha} or IFN-{gamma} on CFU-GM and BFU-E progenitors (Fig. 3Go, A and B), indicating that activation of p38{alpha} and/or p38{beta} is (are) essential for the induction of the inhibitory effects of these cytokines on human hemopoiesis. In contrast, PD98059, a mitogen-activated protein/extracellular signal-related kinase (MEK kinase) inhibitor which blocks extracellular signal-related kinase (Erk) but not p38 activation, had no effects on TNF-{alpha}-dependent hemopoietic suppression (Fig. 3GoC), indicating that the Erk pathway is not required for such an effect. Similarly, SB202474 had no effects on TNF-{alpha}-dependent hemopoietic suppression (Fig. 3GoD).



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  		FIGURE 3. TNF-{alpha} and IFN-{gamma} inhibit the growth of human bone marrow-derived hemopoietic progenitors and induce apoptosis, in a p38-dependent manner. A, Bone marrow mononuclear cells were plated in methylcellulose, in the presence or absence of the indicated doses of TNF-{alpha} (nanograms per milliliter) (A) or IFN-{gamma} (1000 IU/ml) (B) and the p38 inhibitor SB203580 (SB; 10 µM). Data are expressed as percent control of CFU-GM or BFU-E colony numbers for untreated cells. Means + SE of three independent experiments for each condition are shown. C, Bone marrow mononuclear cells were plated in methylcellulose, in the presence or absence of TNF-{alpha} (nanograms per milliliter) and the MEK1 kinase inhibitor PD098059 (PD; 10 µM). Data are expressed as percent control of CFU-GM or BFU-E colony numbers for untreated cells. Means + SE of three independent experiments for each condition are shown. D, Human bone marrow mononuclear cells were plated in methylcellulose, in the presence or absence of TNF-{alpha} (nanograms per milliliter) and the structural analog SB202474, as indicated. Data are expressed as percent control of CFU-GM or BFU-E colony numbers for untreated cells. Means + SE of two independent experiments for each condition are shown. E, Isolated bone marrow CD34+ cells were cultured for 4 days in the presence and absence of 1000 IU/ml IFN-{gamma} or 20 ng/ml TNF-{alpha}. Cells were analyzed for apoptosis by flow cytometry after staining with an Ab against annexin V. Data are expressed as mean + SE from two independent experiments for percent annexin V-positive cells.

 
We subsequently performed studies to determine whether p38 mediates proapoptotic signals in CD34+ hemopoietic precursors. Bone marrow-derived CD34+ cells were incubated with IFN-{gamma} or TNF-{alpha}, in the presence or absence of SB203580, and the induction of apoptosis was evaluated by annexin V staining. TNF-{alpha} or IFN-{gamma} treatment resulted in apoptosis of CD34+ progenitor cells (Fig. 3GoE). Such apoptosis was partially reversed by pretreatment with SB203580 (Fig. 3GoE), indicating that the SB203580-dependent reversal of the myelosuppressive effects of these cytokines is mediated, at least in part, by inhibition of apoptosis.

Several previous studies have shown that TNF-{alpha} and IFN-{gamma} are overproduced by marrow and/or peripheral blood mononuclear cells isolated from aplastic anemia patients and that high levels of these cytokines are detectable in the blood and/or bone marrow sera from these patients (1, 2, 3, 4, 5, 6, 7, 8). Furthermore, previous studies have shown that addition of neutralizing anti-IFN-{gamma} Abs in aplastic anemia marrows increases hemopoietic progenitor colony formation (reviewed in Refs. 1, 2, 3, 4). Because our data indicated that activation of p38 is essential for the generation of the inhibitory effects of TNF-{alpha} and IFN-{gamma} on normal hemopoiesis, we examined the potential role of this pathway in the pathogenesis of aplastic anemia. Four patients with severe aplastic anemia were studied. The clinical characteristics of the patients at the time of the studies are summarized in Table IGo. Bone marrow mononuclear cells from these patients were cultured in methylcellulose in the presence or absence of the p38-specific inhibitor SB203580 or the MEK kinase inhibitor PD98059, used as a control. As expected, BFU-E and CFU-GM colony formation was severely suppressed in all patients (Fig. 4Go). Addition of SB203580 to the cultures resulted in a substantial increase in colony formation in all cases, whereas addition of PD98059 had no significant effects (Fig. 4Go). Thus, pharmacological inhibition of p38 in aplastic anemia bone marrows partially reverses the hemopoietic defect, indicating a critical role for this kinase in mediating myelosuppressive signals.


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  		Table I. Clinical characteristics of patients with aplastic anemia at the time of the studies

 


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  		FIGURE 4. Pharmacological inhibition of p38 increases hemopoietic progenitor colony formation from aplastic anemia bone marrows. Bone marrow mononuclear cells from four patients with severe aplastic anemia were plated in a methylcellulose culture assay system, in the presence or absence of the indicated doses of p38 inhibitor SB203580 (sb; micromolar) or the MEK inhibitor PD098059 (pd; micromolar). Erythroid (BFU-E) or myeloid (CFU-GM) colonies were scored on day 14 of the methylcellulose culture.

 
Aplastic anemia is characterized by a severe hemopoietic defect of all lineages, associated with decreased numbers of CD34+ stem cells (18). It is generally accepted that immune mechanisms play a pivotal role in the pathogenesis of the disease. IFN-{gamma} and TNF-{alpha} have been implicated as the primary cytokines mediating stem cell suppression, although it is likely that other yet unknown cytokines are also involved (1, 2, 3, 4, 5, 6, 7, 8). Interestingly, IFN-{gamma} and TNF-{alpha} exhibit synergistic effects in the suppression of hemopoiesis, which appears to be in part mediated by the IFN-{gamma}-dependent increase in Fas expression on CD34+ marrow progenitor cells and by the IFN-{gamma}-inducible secretion of TNF-{alpha} by macrophages (19, 20).

Despite the well-documented roles of IFN-{gamma} and TNF-{alpha} in the pathogenesis of bone marrow failure in humans, the precise mechanisms by which these cytokines block the growth of bone marrow progenitors remain unknown. In the present study, we provide strong evidence that these cytokines activate the p38 Map kinase pathway in primary human hemopoietic progenitors and that pharmacological inhibition of p38 abrogates their suppressive effects on hemopoiesis. We also demonstrate that such effects occur in part by reversal of the apoptosis of human hemopoietic progenitors induced by these cytokines. This is particularly interesting, given that it has been postulated that an increased rate of apoptosis of CD34+ stem cells accounts for the hemopoietic stem cell defect in aplastic anemia (21). However, other p38-dependent mechanisms may be also contributing. For instance, recent studies have shown that p38 is involved in cell cycle arrest after UV irradiation via regulation of phosphorylation of cdc25B on serine residues 309 and 361 (22). Although there is no direct evidence at this time, it is possible that p38-mediated cell cycle arrest may also be a contributing factor in the induction of bone marrow failure.

Independently of the precise mechanisms involved, our data clearly establish that the p38-specific inhibitor SB203580 increases hemopoietic colony formation from aplastic anemia bone marrows. This inhibitor of the p38 pathway exhibits selectivity for the p38{alpha} and p38{beta} isoforms of the kinase, and it does not inhibit the p38{gamma} and p38{delta} isotypes (23, 24). The basis for the selectivity that this inhibitor exhibits for p38 has been previously established by x-ray and crystallographic studies (25). Nevertheless, we cannot absolutely exclude the possibility that the effects of the inhibitor on aplastic anemia hemopoietic progenitors result in part by inhibition of activation of another yet unknown member of the same family of kinases. Independently of the specific target, our data establish for the first time that a kinase inhibitor can result in an increase in hemopoiesis from aplastic anemia bone marrows in vitro. This raises the possibility that pharmacological inhibitors of p38 and other pyridinylimidazole compounds of the same family may prove useful in the treatment of patients with aplastic anemia and other bone marrow failure states, and future studies in that direction are warranted.


   Acknowledgments
 
We thank Dr. Eleanor Fish (University of Toronto) for carefully reading the manuscript.


   Footnotes
 
1 This work was supported by Grant CA77816 from the National Institutes of Health (to L.C.P.), by a Merit Review grant from the Department of Veterans Affairs (to L.C.P.), and by a grant by the American Cancer Society, Illinois Division (to L.C.P.). Back

2 Address correspondence and reprint requests to Dr. Leonidas C. Platanias, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Olson 8250, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: l-platanias{at}northwestern.edu Back

3 Abbreviations used in this paper: BFU-E, burst forming unit-erythroid; CFU-E, CFU-erythroid; Map, mitogen-activated protein; Erk, extracellular signal-related kinase; MEK, Map/Erk. Back

Received for publication February 14, 2002. Accepted for publication April 23, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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