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Endocrinology Vol. 145, No. 7 3101-3105
Copyright © 2004 by The Endocrine Society

BRIEF COMMUNICATION

Tumor Necrosis Factor {alpha} Inhibits Insulin-Like Growth Factor I-Induced Hematopoietic Cell Survival and Proliferation

Wen Hong Shen, Jian-Hua Zhou, Suzanne R. Broussard, Rodney W. Johnson, Robert Dantzer and Keith W. Kelley

Laboratory of Immunophysiology (W.H.S., J.H.Z., S.R.B., K.W.K.) and Laboratory of Integrative Biology (R.W.J.), Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801; and Integrative Neurobiology, French Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Bordeaux 2, Institut François Magendie des Neurosciences (R.D), 33077 Bordeaux Cedex, France

Address all correspondence and requests for reprints to: Dr. Keith W. Kelley, University of Illinois, Laboratory of Immunophysiology, Department of Animal Sciences, 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, Illinois 61801. E-mail: kwkelley{at}uiuc.edu.

Abstract

Proinflammatory cytokines, such as TNF{alpha} and IL-1ß, are both cytostatic and cytotoxic. In contrast, IGF-I promotes proliferation and survival of hematopoietic progenitor cells. In this report, we establish that both the cytostatic and cytotoxic activity of TNF{alpha} on murine myeloid progenitor cells is only evident in the presence of IGF-I. We first confirmed that IGF-I (100 ng/ml) increases DNA synthesis and reduces apoptosis in murine myeloid progenitor cells induced to die by growth factor withdrawal. TNF{alpha} inhibits, in a dose-dependent fashion from 0.1 to 10 ng/ml, both activities of IGF-I. TNF{alpha} activity was not detected in the absence of IGF-I. Another proinflammatory cytokine, IL-1ß, did not inhibit IGF-I-induced activity in murine factor-dependent cell progenitor-1/Mac-1 cells. However, the ability of TNF{alpha} to impair IGF-I-induced DNA synthesis in human promyeloid cells extends to IL-1ß. Statistically significant inhibition of all these events occurs at very low concentrations of 1 ng/ml or less. These results support the general concept that proinflammatory cytokines impair the actions of hormones on hematopoietic cells, leading to IGF-I receptor resistance.

TNF{alpha} CONCENTRATIONS INCREASE during a number of physiological states, such as aging and obesity, as well as in a variety of pathological conditions, including dementia, cachexia, AIDS, and advanced cancers. All of these diseases are characterized by a reduction in metabolism at some stage of the disease, leading to reduced growth in pediatric patients and frank loss of weight in adult or aged subjects. Extreme cases of growth retardation are caused by loss or reduced expression of two proteins that control over 80% of postnatal growth, GH and IGF-I (1). However, both reduced growth and wasting are often unrelated to GH/IGF-I concentrations in plasma (2). These findings suggest that some disease states can cause certain biological systems to become less sensitive to GH/IGF-I. We recently established that TNF{alpha} induces IGF-I receptor resistance in human breast cancer cells (3, 4), murine myoblasts (5), and neurons (6). However, the possibility that proinflammatory cytokines somehow interact with hormones from the endocrine system to regulate bone marrow-derived hematopoietic cells has not been explored.

GH and IGF-I stimulate hematopoiesis in vivo (7), probably by targeting hematopoietic progenitor cells of both the myeloid and lymphoid lineages (8, 9). GH induces expression of IGF-I in T-helper, T-cytotoxic, and B-cell leukocyte subsets (10). This paracrine IGF-I is biologically important because an antibody to the IGF-I receptor blocks the increase in differentiation of both erythropoietic and granulopoietic colonies caused by GH in human bone marrow (11). Indeed, we have shown that IGF-I promotes the survival (12) and differentiation (13) of myeloid progenitor cells.

Loss of hematopoietic cells and accumulation of fatty tissue in both the bone marrow (14) and thymus gland (15) are distinctive characteristics in aged humans and animals. Hematopoietic progenitors express receptors for GH and IGF-I, as well as for the proinflammatory cytokines TNF{alpha}. Furthermore, adipocytes are now considered to be endocrine cells that synthesize and secrete a variety of cytokines, including TNF{alpha} (16). Production and cytotoxic activity of adipose tissue-derived TNF{alpha} increases in aged rats (17), and TNF{alpha} regulates various aspects of hematopoiesis. For example, mice deficient in the p55 subunit of the TNF receptor display an increase in bone marrow cellularity as well as the number of myeloid and erythroid colony-forming progenitor cells (18). Unfortunately, the mechanisms that are responsible for this negative regulation of hematopoietic progenitors by TNF{alpha} are unknown. In this report, we demonstrate that, in the absence of IGF-I, neither TNF{alpha} nor IL-1ß inhibits DNA synthesis in human myeloid progenitor cells. Instead, the cytostatic properties of these proinflammatory cytokines are manifested only when myeloid progenitors are simultaneously exposed to IGF-I.

Materials and Methods

Cell culture and reagents
Murine factor-dependent cell progenitor-1/Mac-1 (FDCP) cells were kindly provided by Dr. L. Rohrschneider (Fred Hutchinson Cancer Center, Seattle, WA) and maintained in RPMI 1640 medium (MediaTech, Herndon, VA) supplemented with 10% heat-inactivated equine serum (HyClone, Logan, UT) and 2.5 U/ml recombinant murine IL-3 (BioSource, Camarillo, CA) at 37 C with 95% humidity and 7% CO2. Human promyeloid HL-60 cells were purchased from the American Type Culture Collection (ATCC, Manassas, VA) and cultured in maintenance medium consisting of Eagle’s MEM supplemented with 10% fetal bovine serum (FBS, HyClone). For experimentation, cells were grown in culture media, RPMI 1640 without equine serum, or IL-3 for FDCP cells and MEM without FBS for HL-60 cells, both supplemented with 5 µg/ml of human transferrin and 30 nM of sodium selenite. Recombinant human IGF-I and murine and human TNF{alpha}, and IL-1ß were purchased from Intergen (Purchase, NY).

DNA synthesis
FDCP cells were washed three times (400 x g, at room temperature) and plated into 96-well plates (Costar 3596, Corning, NY) at a density of 2 x 104 cells/200 µl per well in serum-free culture medium. Cells were treated in triplicate with different concentrations of murine TNF{alpha} with or without 100 ng/ml of IGF-I for 6 h before DNA labeling with [methyl-3H]thymidine (1 µCi per well; 1 Ci = 37 GBq; ICN, Costa Mesa, CA) for an additional 12 h. For HL-60 cells, after 24 h incubation in serum-free culture medium, cells were treated with different concentrations of human TNF{alpha} or IL-1ß in the presence or absence of IGF-I (100 ng/ml) for 30 h and pulsed with [3H]thymidine (1 µCi per well) for another 6 h. After pulsing, FDCP and HL-60 cells were harvested immediately onto glass microfiber filters (Whatman 934Aht) with a PHD cell harvester (Cambridge Technology, Cambridge, MA). The filters were dried and then submerged into 3 ml of scintillation fluid, and [3H] radioactivity was determined with a Beckman (Fullerton, CA) LS 6000IC scintillation counter. This technique of measuring IGF-I-induced DNA synthesis closely tracks the proportion of cells in the S phase of the cell cycle in both HL-60 (19) and MCF-7 cells (3).

Apoptosis
Translocation of phosphatidylserine to the outer layer of the cell membrane is an early event that occurs during apoptotic cell death (20). ApoAlert Annexin V-fluorescein isothiocyanate (FITC) (CLONTECH, Palo Alto, CA) was used to bind exposed phosphatidylserine on apoptotic FDCP cells treated with IGF-I (100 ng/ml) in the presence or absence of different concentrations of TNF{alpha} for 10 h. Annexin V-FITC-positive cells were quantified on an EPICS XL flow cytometer (Coulter, Miami, FL).

Statistical analysis
Statistical analyses were performed using the Statistical Analysis System for Windows (21). All data were analyzed as a completely randomized design using standard ANOVA procedures. Treatment differences were assessed by Duncan’s multiple range tests. All experiments were independently replicated at least three times, and data were summarized as means ± SEM. Two-sided P values of P < 0.05 (*) or P < 0.01 (**) were considered statistically significant.

Results

TNF{alpha} dose-dependently reduces IGF-I-induced DNA synthesis and cell survival in murine progenitor myeloid cells
We recently demonstrated that the cytostatic properties of TNF{alpha} on MCF-7 breast cancer cells could be detected only in the presence of IGF-I (3). To determine whether TNF{alpha} also induces IGF-I receptor resistance in hematopoietic cells, we measured DNA synthesis in FDCP murine promyeloid cells. We have previously established from IGF-I dose response studies that maximal survival and proliferative responses of FDCP cells occur at 100 ng/ml (12). Compared with cells incubated in medium alone for 18 h, IGF-I caused a 5.5-fold increase of [3H]thymidine incorporation into DNA (Fig. 1AGo). Although TNF{alpha} alone neither increased nor decreased DNA synthesis, cotreatment with TNF{alpha} dose-dependently suppressed the ability of IGF-I to promote DNA synthesis. TNF{alpha}, at a concentration of 1 ng/ml, inhibited (P < 0.01) the ability of IGF-I to increase DNA synthesis. Because we used an optimal concentration of IGF-I, it is possible that greater inhibition by TNF{alpha} would occur at suboptimal concentrations of IGF-I.



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  		FIG. 1. TNF{alpha} dose-dependently impairs IGF-I-induced DNA synthesis and cell survival in murine progenitor myeloid cells. A, DNA synthesis was measured by [3H]thymidine incorporation in murine FDCP myeloid progenitor cells treated with increasing concentrations (nanograms per milliliter) of murine TNF{alpha} in the presence and absence of IGF-I (100 ng/ml). Results are expressed as the mean ± SEM of three independent experiments. **, P < 0.01. B, FDCP progenitor myeloid cells were treated with increasing concentrations (ng/ml) of murine TNF{alpha} separately or in combination with 100 ng/ml of IGF-I. Cells undergoing early apoptotic cell death were detected using annexin V-FITC followed by flow cytometric analysis. A representative histogram from flow cytometric measurements of annexin V labeling of FDCP cells is shown, followed by a statistical summary of three independent experiments. **, P < 0.01.

 
IGF-I significantly reduces the proportion of apoptotic FDCP (12) and HL-60 (13) cells, defined as those that have a heightened fluorescence signal for Hoechst 33342 but are negative for propidium iodide. Here we used the more specific and definitive technique consisting of an annexin V-FITC conjugate that binds to phosphatidylserine residues that become exposed on the cell surface during the early phases of apoptotic cell death. This technique detects very early apoptotic cells, occurring before DNA strand fragmentation (20). We detected 63 ± 4% annexin V-positive FDCP cells after 10 h of growth factor deprivation. As expected, IGF-I significantly reduced the population of annexin V-positive apoptotic cells to 12 ± 1% (P < 0.01). TNF{alpha} alone did not change the apoptotic population, even at the highest concentration of that was tested (data not shown). The interesting finding occurred in cells that were simultaneously exposed to both IGF-I and TNF{alpha}. A representative example is shown in Fig. 1BGo, followed by a summary of three independent experiments. It was only in this situation that a dose-dependent biological effect of TNF{alpha} could be detected. The proportion of apoptotic cells rose from 12 ± 1% to 14 ± 1% with 0.1 ng/ml TNF{alpha}, to 16 ± 1% with 1 ng/ml TNF{alpha} (P < 0.01) and to 20 ± 1% with 10 ng/ml of TNF{alpha} (P < 0.01). Addition of murine IL-1ß at concentrations ranging from 0.1–100 ng/ml, in either the absence of presence of IGF-I, did not affect DNA synthesis or growth factor-induced apoptosis (data not shown). The reason for this negative result is not known, but it could be due to very low expression of any isoform of IL-1 receptors on murine FDCP cells.

TNF{alpha} and IL-1ß inhibit IGF-I-induced DNA synthesis in human promyeloid HL-60 cells
Human HL-60 promyeloid cells survive for more than 48 h in serum-free medium, with 5% or less displaying apoptotic markers (13). Because we have established that IGF-I significantly increases both DNA synthesis (22) and number (19) of HL-60 cells, they were treated with increasing concentrations of TNF{alpha} in the presence or absence of IGF-I. Compared with cells cultured in medium alone for 36 h, IGF-I (100 ng/ml) increased [3H]thymidine incorporation by over 8-fold (Fig. 2AGo). Once again, TNF{alpha} alone had no significant effect on DNA synthesis. However, in the presence of IGF-I, TNF{alpha} dose-dependently reduced DNA synthesis. Indeed, cotreatment with as little as 0.1 ng/ml of TNF{alpha} significantly (P < 0.05) suppressed IGF-I induction of DNA synthesis and 10 ng/ml of TNF{alpha} caused over a 60% reduction (P < 0.01). In the absence of IGF-I, very few HL-60 cells died (<10% propidium iodide positive), and addition of IGF-I or TNF{alpha}, either alone or in combination, did not affect cell survival.



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  		FIG. 2. TNF{alpha} inhibits IGF-I-induced DNA synthesis in human promyeloid HL-60 cells, and another proinflammatory cytokine, IL-1ß, has similar effects. HL-60 cells were treated with increasing concentrations of human TNF{alpha} (A) or IL-1ß (B) in the presence and absence of IGF-I (100 ng/ml) for 30 h followed by DNA labeling with [3H]thymidine for additional 6 h. Fold induction in [3H]thymidine incorporation was determined and mean values ± SEM of three separate experiments are represented in graphs A and B. *, P < 0.05; **, P < 0.01.

 
We then determined whether the inhibitory property of TNF{alpha} on IGF-I-induced DNA synthesis extends to human IL-1ß, as it does to human MCF-7 breast cancer cells (3). We found a similar dose-dependent inhibitory property of IL-1ß on IGF-I-induced DNA synthesis (Fig. 2BGo). The 9-fold induction of DNA synthesis caused by IGF-I was significantly inhibited by as little as 0.1 ng/ml of IL-1ß (P < 0.05). As with TNF{alpha}, addition of IL-1ß alone did not affect survival of HL-60 cells.

Discussion

We recently established a human breast cancer cell model in which proinflammatory cytokines suppress IGF-I-induced cell cycle progression (3). In this system, we have now identified some intracellular signaling proteins that mediate the interaction between proinflammatory cytokines and IGF-I (4). Although coexpression of receptors for IGF-I and TNF{alpha} on hematopoietic progenitors offer the possibility for cross talk between the endocrine and immune systems, it is unknown whether proinflammatory cytokines suppress survival and proliferation of myeloid progenitors by inhibiting the action of IGF-I, thereby leading to IGF-I receptor resistance. In this report, we provide evidence revealing a potentially important interaction between proinflammatory cytokines and IGF-I in myeloid progenitor cells. In this scenario, IGF-I-induced DNA synthesis is inhibited by TNF{alpha} in promyeloid cells of both murine (Fig. 1AGo) and human origin (Fig. 2AGo). This inhibitory property of TNF{alpha} on human promyeloid cells, but not on murine promyeloid cells, is shared by another proinflammatory cytokine, IL-1ß (Fig. 2BGo). Moreover, IGF-I protects murine myeloid progenitor cells from apoptotic cell death induced by growth factor withdrawal, and this antiapoptotic property of IGF-I is impaired by TNF{alpha} (Fig. 1BGo). It is important to note that the inhibitory properties of both TNF{alpha} and IL-1ß on human myeloid progenitor cells are detectable only when cells are simultaneously exposed to IGF-I. These results are consistent with our findings in human breast cancer epithelial cells (3), murine myoblasts (5), and murine cerebellar granular neurons (6), suggesting a novel model for cytokine-induced IGF-I resistance.

A wealth of in vivo evidence indicates that IGF-I acts on a variety of hematopoietic progenitors to promote their survival, proliferation and differentiation. Intraperitoneal injections of either GH (23) or IGF-I (24) into mice cause significant increases in bone marrow and splenic hematopoietic progenitor cells and reverse the myelosuppressive properties of azidothymidine. IGF-I stimulates proliferation (25) and differentiation of progenitor B cells, as assessed by expression of cytoplasmic µ-heavy chains (26). Similarly, thymic pre-T cells proliferate in response to IGF-I (27). These hematopoietic-promoting properties of IGF-I on progenitor cells have recently been extended to the central nervous system, where oligodendrocyte progenitor survival, proliferation and remyelination are largely inhibited in mice with a mutant form of the IGF-I receptor after a demyelinating lesion (28). This discovery is consistent with the finding that IGF-I promotes Schwann cell myelination of mice dorsal root ganglion axons (29). The present results confirm the potent ability of IGF-I in promoting both myeloid progenitor cell DNA synthesis and survival.

A novel aspect of this report is that no biologic activity of the two major proinflammatory cytokines, TNF{alpha} or IL-1ß, could be detected in the absence of IGF-I. Adipocytes accumulate in both the bone marrow (14) and thymus glands (15) of aged humans and animals, which may serve as a local source of TNF{alpha}. TNF{alpha} inhibits colony formation of murine granulocyte-macrophage progenitor cells (30) and proliferation of bone marrow progenitor cells (31). However, in all of these experiments, progenitor cells were cultured in a medium containing at least 10% FBS, which typically contains at least 200 ng/ml of IGF-I (32). It is therefore possible that TNF{alpha} suppresses hematopoiesis induced by growth factors contained in FBS. This confounding variable of unknown growth factors was controlled in the present experiments by using a defined medium that contained no growth promotants.

Collectively, these data establish that low concentrations of TNF{alpha} impair the ability of IGF-I to induce DNA synthesis in myeloid progenitor cells of both murine and human origin. IL-1ß acts like TNF{alpha} on human, but not murine, promyeloid cells. The cytostatic properties of both TNF{alpha} and IL-1ß are undetectable in the absence of IGF-I. A recent report used a variety of well-established in vivo tumor models to show that the IGF-I receptor could be used as broad spectrum therapeutic target for a number of malignancies (33). Data in this manuscript show that proinflammatory cytokines induce IGF-I receptor resistance in vitro, suggesting that these immune-derived proteins might also be targeted to tumor sites to impair cancer cell growth or induce cancer cell death. Therefore, this report offers support for the evolving concept that proinflammatory cytokines from the immune system regulate a number of biological systems by interfering with the actions of endocrine-derived growth factors and hormones.

Footnotes

This work was supported by National Institutes of Health Grant AI50442 (to K.W.K.).

Abbreviations: FBS, Fetal bovine serum; FDCP, murine factordependent cell progenitor-1/Mac-1; FITC, fluorescein isothiocyanate.

Received February 25, 2004.

Accepted for publication April 2, 2004.

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