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The Journal of Immunology, 1998, 160: 906-910.
Copyright © 1998 by The American Association of Immunologists

CXC Chemokines Suppress Proliferation of Myeloid Progenitor Cells by Activation of the CXC Chemokine Receptor 21

Ximena Sanchez, Katsutoshi Suetomi, Beth Cousins-Hodges, Julie K. Horton2 and Javier Navarro3

Department of Physiology and Biophysics and the Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, TX 77555


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
IL-8 is one of the major mediators of the transendothelial migration of neutrophils from the circulation to the site of injury and infection. In this work we demonstrate that the CXC or {alpha}-chemokines, IL-8 and melanoma growth stimulatory activity (MGSA) induce myeloid suppression via direct action on progenitor cells, mediated by activation of the murine homologue of the CXC chemokine receptor-2 (CXCR2) or IL-8R B. We first show that proliferation of the IL-3-dependent murine myeloid progenitor cell line 32D is suppressed by human IL-8 and the functionally and structurally related peptide, MGSA. Second, we show for the first time the high endogenous expression of the murine CXCR2 in 32D cells, as demonstrated by Northern blot analysis, binding to [125I]macrophage inflammatory protein-2, and macrophage inflammatory protein-2-induced calcium responses in 32D cells. Third, we demonstrate that IL-8 and MGSA induce a rise in intracellular calcium in 32D cells. The IL-8-induced Ca2+ response is desensitizing, since a second dose of IL-8 did not trigger a second calcium response. Other chemokines, including neutrophil-activating protein-2, platelet factor-4, RANTES, and macrophage chemotactic protein-1, neither suppressed the proliferation of 32D cells nor induced a rise in intracellular calcium. Finally, the IC50 of IL-8- and MGSA-dependent suppression of proliferation of 32D cells is in good agreement with the EC50 of IL-8- and MGSA-dependent activation of neutrophil Mac-1 up-regulation and chemotaxis. Our studies are consistent with the idea that IL-8 and MGSA suppress the proliferation of 32D cells by activation of murine CXCR2.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Cytokines modulate myelopoiesis by promoting or suppressing the proliferation and differentiation of myeloid progenitor cells. In contrast to the growth-promoting cytokines, the transmembrane signaling mechanisms of growth-suppressing cytokines are poorly understood. Exposure of bone marrow cells to chemokines (e.g., IL-8 and macrophage inflammatory protein-1 (MIP-1)4) suppressed the proliferation of myeloid progenitor cells (1). Whether chemokines are acting on progenitor cells or on stromal cells of the bone marrow remains to be determined. Although previous studies have shown that several chemokines suppressed the proliferation of highly purified primary progenitor cells (2), the low frequency and heterogeneity of progenitor cells from bone marrow has precluded the determination of the transmembrane signaling mechanisms of chemokines that suppress the proliferation of progenitor cells.

Two major subfamilies of chemokines are distinguished on the basis of whether the first two cysteines are separated by a single residue (CXC or {alpha}-chemokines) or whether they are adjacent (CC or ß-chemokines) (3). Chemokine receptors belong to the superfamily of G protein-coupled receptors encoded by cellular and viral genomes (4). The best characterized CXC chemokine is IL-8, a 72-amino acid peptide secreted in response to injury and infection. Multiple receptors have been identified to bind IL-8. Thus, IL-8 mediates the migration of neutrophils from the circulation to the site of injury by activation of IL-8R, subtypes A and B, or CXC chemokine receptors 1 and 2 (CXCR1 and CXCR2) (5, 6, 7). The human CXCR1 binds with high affinity to IL-8 and with low affinity to the structurally related CXC chemokines melanoma growth stimulatory activity (MGSA) and neutrophil-activating peptide-2 (NAP-2). The human CXCR2 binds with high affinity to IL-8 and MGSA and with moderate affinity to NAP-2 (8). In contrast, murine neutrophils apparently express only the murine homologue of CXCR2. This receptor exhibits high affinity toward murine CXC chemokines MIP-2 and platelet-derived growth factor (PDGF) inducible gene, but low affinity to human IL-8 (9, 10, 11, 12). Additionally, IL-8 is angiogenic and mitogenic for endothelial cells (13); however, the IL-8R subtype that mediates these effects is unknown. Both CXC and CC chemokines bind to the Duffy Ag of RBC (14) and to G protein-coupled receptors encoded by viral genomes. For example, IL-8 binds with high affinity to a G protein-coupled receptor encoded by Kaposi’s sarcoma B-associated herpes virus (15). Recent studies have suggested that the chemokine receptor that mediates the IL-8-dependent suppression of proliferation of bone marrow-derived progenitor cells appear to be IL-8R B or CXCR2 (16). In this work, we show that IL-8 and MGSA suppress proliferation of the murine myeloid progenitor cell line 32D. The data are consistent with the idea that suppression of the proliferation of progenitor cells by IL-8 and MGSA is mediated by activation of the murine homologue of CXCR2.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cell cultures

The murine IL-3 dependent 32D cell line was provided by Dr. J. Greenberger, University of Pittsburgh Medical School (Pittsburgh, PA). 32D cells were maintained in RPMI 1640 plus 15% heat-inactivated FBS and 15% conditioned medium from the murine myelomonocytic cell line WEHI-3B as a source of crude IL-3 (17). Purified IL-3 was a gift from Amgen, Inc. (Thousand Oaks, CA). Cells were cultured at 37°C in a 5% CO2 atmosphere and were maintained at a cell density of 0.5 x 106 cells/ml. Murine stem cell lines CCE and D3 were obtained from American Type Culture Collection (Rockville, MD) and cultured in DMEM supplemented with 10% FCS and 1000 U/ml of leukemia inhibitory factor (Life Technologies, Grand Island, NY).

Agar colony assays

Cultures of 32D cells were conducted as described by Metcalf (18). In brief, 300 cells were seeded in 35-mm petri dishes containing 1 ml of Iscove’s modified Dulbecco’s medium supplemented with 10% heat-inactivated FBS, 0.3% agar and IL-3, or 10% conditioned medium from the cell line WEHI-3B. Chemokines resuspended in PBS or an equal volume of PBS were added to the empty culture dish before addition of the cell suspension in agar medium. Colonies were scored on days 7 and 14 of culture.

Intracellular calcium measurements

Exponentially growing 32D cells were harvested by centrifugation and resuspended in a solution containing 140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 1 mM NaHPO4, 5 mM glucose, 20 mM HEPES (pH 7.4), 1 mg/ml BSA, and 1 mM probenecid. Cells (107/ml) were loaded with 5 µM of the calcium-sensitive dye indo-1/AM for 1 h at room temperature as previously described (19). Intracellular calcium levels were monitored at 37°C with a spectrofluorometer (Perkin-Elmer 650–10S, Norwalk, CT) using an excitation wavelength of 330 nm and an emission wavelength of 405 nm.

Northern blot analysis

Total RNA extracted from 107 cells using the Ultraspec RNA isolation system (Biotecx Laboratories, Houston, TX) was fractionated on 1% agarose-formaldehyde gels, blotted to nylon membranes, and cross-linked by brief exposure to UV irradiation. Membranes were hybridized to the murine CXCR2 cDNA labeled by the random priming procedure as described by the manufacturer (Pharmacia, Piscataway, NJ).

Expression of murine CXCR2 in COS-7 cells

The cDNA encoding the murine CXCR2 was synthesized by PCR as described previously (9) and subcloned into the expression vector pRC/CMV (Invitrogen, San Diego, CA). COS-7 cells were transiently transfected by the DEAE-dextran procedure using 10 µg of recombinant plasmid (5). Recombinant Tyr-MIP-2 was expressed in Escherichia coli and purified using a heparin column as described previously (20). Labeled [125I]MIP-2 was prepared by the chloramine-T procedure (5). Binding of [125I]Tyr-MIP-2 to transfected COS-7 cells was performed as previously described (8).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
IL-8- and MGSA-induced suppression of proliferation of 32D cells

To elucidate the receptor signaling mechanisms of chemokine-induced suppression of myeloid progenitor cells, it is necessary to characterize tissue culture models of precursor cells that respond to growth factors. For this study, we have chosen the 32D cell line derived from bone marrow myeloid precursor cells. This cell line exhibits many features of normal hemopoietic progenitor cells. In particular, the survival, proliferation, and regulation of the cell cycle of 32D cells requires the presence of CSFs. Additionally, this cell line exhibit clonogenic cell self-renewal (18).

The proliferation of 32D cells is readily monitored by agar colony assays. In Figure 1Go we show that colony formation was dependent upon the concentration of IL-3 in the culture medium. Compact spherical colonies of various sizes were formed after 7 days in culture. No colony formation was observed in the absence of IL-3. Similar colony formations were observed after addition of conditioned medium from cultures of the cell line WEHI-3B, a source of crude IL-3. This result is in good agreement with those of previous studies on the requirement of IL-3 for the proliferation and survival of 32D cells (18). We then tested the effects of recombinant human chemokines on the colony formation of 32D cells. We found that chemokines, including IL-8, MGSA, NAP-2, and RANTES, did not support the proliferation or survival of 32D cells in the absence of IL-3 (data not shown). However, IL-8 and MGSA induced, in a dose-dependent fashion, a marked suppression of colony formation of 32D cells. The estimated ID50 for IL-8 and MGSA were 58 and 55 nM, respectively (Fig. 2Go). Similarly, MIP-2, the murine homologue of MGSA, suppressed the proliferation of 32D cells, although at lower concentrations than IL-8 or MGSA (data not shown). No effects were observed with other chemokines, including NAP-2, platelet factor-4 (PF4), RANTES, and MCP-1. These results are distinct from those studies with myeloid progenitor cells from bone marrow of mice and humans (1, 16). Thus, CXC chemokines (e.g., IL-8, MIP-2, PF4, and IFN-{gamma}-inducible protein and CC chemokines (e.g., MIP-1{alpha} and MCP-1) produced marked suppression of proliferation of progenitor cells derived from murine (BFU-E) granulocyte-macrophage CFU, erythrocyte burst-forming unit, and multipotential CFU granulocyte-erythroid-macrophage-megakaryocyte (CFU-GEMM) (16). The distinct pharmacologic profiles of the 32D cell line vs the heterogeneous population of progenitor cells from bone marrow are most likely due to the expression of chemokine receptors in a cell type-specific fashion. The 32D cell line may have derived from a subset of murine progenitor bone marrow cells that only express receptors for IL-8 and MGSA. Alternatively, the immortalized 32D cells may have lost the receptors for the other suppressive chemokines.



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  		FIGURE 1. IL-3-dependent colony formation of 32D cells. 32D cells (300/dish) were cultured in duplicate in the presence of increasing concentrations of IL-3. After 7 days in culture, the number of colonies containing >50 cells were counted. The maximum number of colonies was similar to that obtained with WEHI-3B-conditioned medium.

 


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  		FIGURE 2. Effects of IL-8 and MGSA on the IL-3-dependent formation of 32D cell colonies. Increasing concentrations of IL-8 (•) and MGSA ({square}) were added to 32D cells in agar cultures (300 cells/dish) in the presence of WEHI-3B-conditioned medium, and after 7 days in culture the number of colonies scored.

 
Expression of murine CXCR2 in 32D cells

Chemokines bind to a subfamily of G protein-coupled receptors that are expressed in a leukocyte-specific fashion. For example, receptors for CXC chemokines, such as IL-8 and MGSA, are highly expressed in neutrophils, whereas receptors for CC chemokines, including RANTES, MIP-1{alpha}, MIP-1ß, and MCP-1, are expressed in monocytes, eosinophils, lymphocytes, and basophils (3). In addition, both CXC and CC chemokines have been shown to bind to the Duffy Ag of RBCs and to receptors encoded by viral genomes (14, 15, 21). It has been argued that separate receptor signal transduction mechanisms mediate the IL-8-induced suppression of proliferation of myeloid progenitor cells and the activation of neutrophils (1, 22). In this work, we examined the expression of the murine homologue of CXCR2 in 32D cells. First, we conducted Northern blot analysis of RNA extracted from the murine stem cell lines CCE and D3, murine neutrophils, and 32D cells, and probed with cDNA encoding the murine CXCR2. As shown in Figure 3Go, the stem cell lines did not express CXCR2 mRNA, whereas neutrophils and 32D cells expressed high levels. The level of expression of CXCR2 mRNA in 32D cells was similar to that in neutrophils. Most importantly, we demonstrate that 32D cells express active CXCR2, since the ligand for the murine homologue of CXCR2, MIP-2, induced a rise in intracellular Ca2+ in a dose-dependent fashion (Fig. 4Go). In addition, the receptor cDNA amplified from RNA from 32D cells appeared to be identical with the murine homologue of CXCR2 that we previously described (9). COS-7 cells transfected with the murine IL-8 receptor exhibited high affinity binding to [125I]MIP-2, with an apparent Ki of 2 nM (Fig. 5Go). This represents the first report demonstrating a high level of expression of CXCR2 in a nonneutrophil cell line. However, trace quantities of CXCR1 and CXCR2 mRNAs have been detected by reverse transcription-PCR in several cell types (23).



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  		FIGURE 3. Expression of a murine homologue of CXCR2 mRNA in 32D cells. Ten micrograms of total RNA was blotted onto nylon membranes and probed with a 32P-labeled cDNA probe encoding the murine homologue of CXCR2. Lanes 1 and 2 contain RNA from 32D and murine neutrophils, respectively. Lanes 3 and 4 contain RNA from stem cell lines CCE and D3, respectively

 


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  		FIGURE 4. MIP-2-induced increase of intracellular calcium in 32D cells. Increasing amounts of recombinant Tyr-MIP-2 were added to 32D cells loaded with indo-1 as described in Materials and Methods. The final concentrations of Tyr-MIP-2 were: a, 2 nM; b, 5 nM; c, 10 nM; d, 20 nM; e, 40 nM; and f,. 60 nM.

 


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  		FIGURE 5. Binding of [125I]Tyr-MIP-2 to COS-7 cells transfected with murine CXCR2 cDNA. Transfected cells were incubated with [125I]Tyr-MIP-2 (1 nM) at 4°C for 2 h in the presence of increasing concentrations of unlabeled Tyr-MIP-2 and IL-8.

 
IL-8- and MGSA-induced activation of the murine homologue of CXCR2 in 32D cells

The high expression of murine CXCR2 mRNA in 32D cells suggests that IL-8 and MGSA mediate myelosuppression via the same receptor that is expressed in neutrophils. In Figure 6Go, we show that IL-8 and MGSA trigger a rise in intracellular calcium in 32D cells. The estimated EC50 for the IL-8-induced rise of intracellular calcium was 25 nM (Fig. 7Go); this agrees with the ID50 for the IL-8-depended suppression of proliferation, suggesting that mobilization of intracellular calcium is one of the signaling mechanisms that regulates the proliferation of 32D cells.



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  		FIGURE 6. IL-8- and MGSA-induced increase of intracellular calcium in 32D cells. IL-8 and MGSA were added at a final concentration of 250 nM to cells preloaded with indo-1.

 


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  		FIGURE 7. Dose response of IL-8-induced increase of intracellular calcium. Increasing amounts of rIL-8 were added to32D cells loaded with indo-1 as described in Materials and Methods. The final concentrations of IL-8 were: a, 10 nM; b, 25 nM; c, 50 nM; d, 125 nM; and e, 250 nM.

 
32D cells pretreated with IL-8 failed to respond to a second dose of IL-8 and addition of MGSA, indicating that IL-8 induced desensitization of the IL-8 receptor. In contrast, cells pretreated with MGSA failed to respond to a second dose of MGSA, but responded well to addition of IL-8. These observations are consistent with our and other recent studies, suggesting that MGSA induces a weaker desensitization signal than IL-8. For example, IL-8 triggers a faster rate of internalization of IL-8R B than MGSA (24, 25), although both IL-8 and MGSA bind IL-8R B with the same affinity. This finding suggests that the signal triggered by MGSA is sufficient to desensitize the MGSA-mediated calcium responses, but not those mediated by IL-8. In contrast, ATP induces a calcium response regardless of whether the cells have been pretreated with IL-8, suggesting that the murine CXCR2 undergoes homologous desensitization (Fig. 8Go). NAP-2, PF4, RANTES, and MCP-1 failed to elicit a calcium response in 32D cells, consistent with their lack of effect on the suppression of proliferation of 32D cells.



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  		FIGURE 8. 32D cells pretreated with pertussis toxin failed to respond to IL-8. IL-8 (250 nM) was added to untreated and pertussis toxin-treated 32D cells loaded with indo-1. The ATP concentration added to the cells was 0.5 mM.

 
In neutrophils, CXCR1 and CXCR2 are coupled to pertussis toxin-sensitive G proteins. We have analyzed the sensitivity of the IL-8-dependent calcium response in 32D cells pretreated with pertussis toxin. Similar to the results obtained in neutrophils, IL-8 fails to induce a rise in intracellular calcium in 32D cells pretreated with pertussis toxin (Fig. 8Go), indicating that the murine homologue of CXCR2 is coupled to Gi proteins. To determine the relative affinities of IL-8 and MGSA to the murine CXCR2, we examined the effect of IL-8 on the binding of recombinant [125I]MIP-2 to COS-7 cells transfected with the murine CXCR2 cDNA. IL-8 weakly displaced [125I]MIP-2 binding (Fig. 5Go). This result is in good agreement with those of previous studies indicating that the murine homologue of CXCR2 exhibits low affinity for human IL-8 (8, 9, 10, 11, 12).

The relationship between the apparent affinity of IL-8 to the murine CXCR2 and the EC50 of the IL-8-dependent suppression of proliferation is consistent with previous studies in murine neutrophils. For example, the apparent Kd of IL-8 binding to murine neutrophils is several orders of magnitude higher than the EC50 of IL-8 for Mac-1 up-regulation and chemotaxis (10). Of importance, IL-8 failed to induce a calcium response in cells pretreated with MIP-2 (Fig. 9Go), indicating that MIP-2 and IL-8 activate the same receptor. This observation plus the good correlation of the pharmacologic profile of chemokine-induced suppression of proliferation of 32D cells with the chemokine-induced calcium responses in 32D cells strongly suggest that IL-8- and MGSA-mediated myeloid suppression is via activation of CXCR2 in 32D cells. Further support for this idea is provided by a recent observation with a cell line derived from 32D named 32D-GR (26) that does not express CXCR2. IL-8, MGSA, and MIP-2 neither induced an increase in intracellular calcium nor suppressed the proliferation of 32D-GR cells (data not shown). These results are in good agreement with a recent report indicating that IL-8 failed to induce myelosuppression of bone marrow cells from mice deficient in CXCR2 (16).



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  		FIGURE 9. MIP-2 desensitized the IL-8 B-dependent calcium response. 32D cells were pretreated with MIP-2 (5 nM), and then IL-8 was added at a final concentration of 250 nM.

 
In conclusion, this work demonstrates that the IL-8-dependent suppression of progenitor cell proliferation is mediated by direct action on the progenitor cells. The data suggest that IL-8 and MGSA promote the suppression of myeloid progenitor cells by triggering a calcium transduction mechanism similar to that induced for neutrophil activation. This cell model should be suitable to examine the downstream molecular mechanisms of the IL-8-dependent suppression of proliferation of progenitor cells.


   Footnotes
 
1 This work was supported by National Institute of Health Grant R01AI34031. Back

2 Present address: Laboratory of Structural Biology, National Institute of Environmental and Health Sciences, Research Triangle Park, NC 27709. Back

3 Address correspondence and reprint requests to Dr. Javier Navarro, Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, TX 77555–0641. E-mail address: Back

4 Abbreviations used in this paper: MIP-1, macrophage inflammatory protein-1; CXCR, CXC chemokine receptor; MGSA, melanoma growth stimulatory activity; NAP-2, neutrophil-activating peptide-2; PF4, platelet factor-4; MCP-1, macrophage chemotactic protein-1. Back

Received for publication June 16, 1997. Accepted for publication September 24, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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N. C. Wilkinson and J. Navarro
PU.1 Regulates the CXCR1 Promoter
J. Biol. Chem., January 1, 1999; 274(1): 438 - 443.
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