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Am J Physiol Heart Circ Physiol 275: H662-H667, 1998;
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Vol. 275, Issue 2, H662-H667, August 1998

Oncostatin M regulates endothelin-1 production in human endothelial cells

Outi Saijonmaa1,2, Tuulikki Nyman1, Päivi Pacek1,2, and Frej Fyhrquist1,2

1 Minerva Institute for Medical Research and 2 Department of Internal Medicine, Helsinki University Central Hospital, SF-00250 Helsinki, Finland

    ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

The effect of the macrophage- and T-lymphocyte-derived cytokine oncostatin M (OSM) on endothelin-1 (ET-1) production in cultured human umbilical cord vein endothelial cells (HUVEC) was studied. OSM (2.5-10 ng/ml) stimulated ET-1 production and the expression of preproendothelin-1 mRNA. The stimulatory effect of OSM was reversed by anti-interleukin (IL)-6 IgG (33 µg/ml). IL-6 (10 ng/ml) was shown to stimulate ET-1 production. The tyrosine kinase inhibitors herbimycin (250-500 ng/ml) and genistein (1-4 µg/ml) suppressed basal ET-1 production and reversed the stimulatory effect of OSM, whereas daidzein (1-8 µg/ml), a less active analog of genistein, had no effect on basal ET-1 production and only partly reversed the stimulatory effect of OSM. The phorbol ester phorbol 12-myristate 13-acetate (PMA) inhibited ET-1 production. Downregulation of protein kinase C (PKC) with PMA (1 µM) preincubation potentiated OSM-induced ET-1 production. In summary, OSM stimulated ET-1 production in cultured HUVEC. The stimulation was probably mediated by IL-6. Furthermore, the present data suggest that tyrosine kinase activation was involved in ET-1 stimulation and that PKC activation leads to suppression of basal and OSM-stimulated ET-1 production.

endothelin-1; human umbilical cord vein endothelial cells; interleukin-6

    INTRODUCTION
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Abstract
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Materials & Methods
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ENDOTHELIN-1 (ET-1) is a vasoconstricting and growth-regulating peptide produced mainly by endothelial cells but also by other cell types including macrophages and epithelial cells (2, 17, 28). ET-1 is the most potent vasoconstrictor peptide so far identified and also has growth-promoting and mitogenic properties. Thus ET-1 may be an important regulatory factor in vascular physiology and pathophysiology (16). Three endothelin peptides have been identified, namely ET-1, ET-2, and ET-3 (12). Only ET-1 is produced by endothelial cells. ET-1 production is modified by various suppressing and stimulating factors. Atrial natriuretic peptide (ANP) and nitrocompounds are suppressors of ET-1 production (25). ET-1 stimulators include thrombin, ANG II, adrenalin, insulin, oxyhemoglobin, shear stress, hypoxia (16) and various cytokines such as tumor necrosis factor-alpha , interleukin (IL)-1beta , interferon-gamma , and transforming growth factor-beta (7, 15).

Cytokines released by leukocytes and endothelial cells mediate leukocyte-endothelial cell interactions and thus regulate vascular function and remodeling. Oncostatin M (OSM) is a cytokine secreted by macrophages and activated T lymphocytes. OSM was first identified by its ability to inhibit growth of human tumor cells (30). OSM affects a variety of normal and tumor cells. OSM is a growth-regulating cytokine, inhibiting or stimulating growth depending on cell type (11). Human endothelial cells express more high-affinity receptors for OSM than nonendothelial cells do (5). OSM stimulates IL-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony stimulating factor, and P-selectin production in cultured human endothelial cells (4, 5, 29). In the present study regulation of ET-1 production by OSM was studied.

    MATERIALS AND METHODS
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Materials & Methods
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Endothelial Cell Culture

Endothelial cells were prepared from human umbilical cord veins according to Jaffe et al. (14). Veins were cannulated, washed with phosphate-buffered saline (PBS), and treated with 0.5% collagenase (Sigma, St. Louis, MO) in PBS for 15 min at room temperature and then collected by centrifugation. Cells were grown to confluence in 0.2% gelatin (Sigma)-coated cell culture flasks (Costar, Cambridge, MA) in medium 199 (GIBCO Laboratories, Belmont, CA) supplemented with 20% fetal calf serum (FCS, GIBCO), 20 µg/ml endothelial cell growth supplement (Sigma), 12 U/ml heparin (Sigma), 100 U/ml penicillin-G, 100 µg/ml streptomycin (GIBCO), and 2 mM L-glutamine (GIBCO) at 37°C in humidified 5% carbon dioxide in air. The cells were detached with 0.125% trypsin-0.02% Na2EDTA solution (GIBCO) and subcultured on 48-well cell culture plates coated with 0.2% gelatin solution. The cells were identified as endothelial cells by their typical cobblestone appearance and the presence of von Willebrand factor with the immunofluorescence method using rabbit immunoglobulins to human von Willebrand factor (Dakopatts, Glostrup, Denmark). More than 90% of the cells stained positively.

Experimental Design

Confluent subcultures (at passages 1-2) were incubated for 24 h with medium 199 supplemented with 5% FCS with or without the following substances, which were all purchased from Sigma: OSM (2.5-10 ng/ml), IL-6 (1-10 ng/ml), anti-human IL-6 IgG fraction, (3.3-33 µg/ml), superoxide dismutase (SOD, 20-200 U/ml), herbimycin (250-500 ng/ml), genistein (2-4 µg/ml), or daidzein (2-4 µg/ml). Cells were preincubated with herbimycin, genistein, or daidzein for 15 min before OSM was added. To downregulate protein kinase C (PKC), we preincubated the cells with phorbol 12-myristate 13-acetate, (PMA, 1 µM) for 24 h before the experiment. Downregulation of PKC was confirmed by using 1 µM PMA as a negative control during the experiment. After 24-h incubation time ET-1 assay was performed as described below.

To exclude the possibility that OSM cross-reacted with anti-human IL-6, 125I-labeled IL-6 together with growing concentrations of OSM were incubated with anti-human IL-6 (33 µg/ml) for 24 h, and then anti-human IL-6 was precipitated using a second antibody (Peninsula). Radioactivity bound was counted in a gamma counter.

Cell Proliferation/Cytotoxicity Assay

Cellular viability and growth were tested by trypan blue exclusion and by [3H]thymidine incorporation. Confluent endothelial cell cultures were incubated with or without the test substances in medium 199 5% FCS with [3H]thymidine (0.4 µCi/ml). After 24-h incubation, cell layers were washed with PBS, incubated with 5% TCA for 5 min, and then dissolved in 0.1 N NaOH. Radioactivity was determined by scintillation counter (Wallac, Turku, Finland).

Measurement of ET-1

Culture medium from endothelial cells was subjected to ET-1 radioimmunoassay, which was performed as described earlier (8) using synthetic ET-1 (Peptide Institute, Barnet, UK) and ET-1 antiserum generated in rabbits with ET-1 coupled by glutaraldehyde to keyhole limpet hemocyanin (Sigma) as an immunogen. The antiserum showed 100% cross-reaction with ET-2 and ET-3 (human; Peninsula, London, UK) and <0.1% cross-reaction with the 20-50, 74-91, and 171-201 sequences of preproendothelin (Peptide Institute); Big ET-(1---38) and Big ET-(22---38) (human; Peninsula); ANP-(1---28) (human; Peninsula); ANG II (Schwarz-Mann, St. Louis, MO); and [Arg8]vasopressin (Ferring, Malmö, Sweden).

Preproendothelin-1 mRNA Measurement

Endothelial cells grown on gelatin-coated cell culture flasks were incubated with OSM (2.5 ng/ml) for 4 h. Total RNA from endothelial cells was isolated by a guanidinium thiocyanate method (6).

Preparation of antisense 32P-labeled ribopropes. ET-1 and beta -actin probes were generated by RT-PCR using human endothelial cell RNA. The T7 promoter sequence was appended to the antisense PCR primers and incorporated into the PCR product. The primer sites for beta -actin were located at nucleotides 87-108 and 314-331 (21) and for ET-1 at nucleotides 157-186 and 474-491 (13). 32P-labeled riboprobes were transcribed with T7 RNA polymerase using Maxiscript in vitro transcription kit (Ambion, Austin, TX). The transcription with T7 polymerase generated a 340-base pair (bp) riboprobe for ET-1 (334-bp protected length) and a 250-bp riboprobe for beta -actin (244-bp protected length). The transcription reaction was incubated for 60 min at 37°C, and the DNA was digested with DNase for 15 min at 37°C. The full-length 32P-labeled riboprobes were separated by electrophoresis in 8 M urea-5% polyacrylamide gel, excised from the gel, and eluted into 300 µl buffer (RPA II Kit, Ambion) overnight. The specific activities of the probes were 5.3 × 108 counts per minute (cpm)/µg and 0.4 × 108 cpm/µg for ET-1 and beta -actin, respectively.

RNase protection assay. Solution hybridization RPA was carried out using RPA II Rnase protection assay kit (Ambion) following the manufacturer's instructions. In brief, sample RNA (7 µg) with 1 × 105 cpm of gel-purified, high-specific-activity ET-1 riboprobe and 2.5 × 104 cpm of beta -actin riboprobe were coprecipitated for 30 min at -20°C. The resulting pellet was resuspended in 20 µl of hybridization buffer, denatured, and incubated overnight at 42°C. After hybridization the samples were digested with 1:100 dilution of RNase (combination of RNase A and RNase T1 in Ambion digestion buffer) for 30 min at 37°C. The protected RNA was precipitated and resuspended in 8 µl of gel-loading buffer. The samples were denatured and resolved by electrophoresis on 5% polyacrylamide-8 M urea gels. The bands were visualized by autoradiography for 12-24 h and quantitated by densitometry. The results for ET-1 were normalized for the amount of beta -actin measured simultaneously in each sample.

Statistical Evaluation

Results are expressed as means ± SE of four to six replicate determinations from three to six separate experiments. Student's t-test for paired or unpaired observations was applied.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

HUVEC appear to secrete ET-1 only (25). The average ET-1 concentration in cell culture medium of untreated endothelial cells was 392 ± 27 pg/ml after 24 h .

OSM (2.5-10 ng/ml) dose dependently increased ET-1 release (Fig. 1A) and preproendothelin-1 mRNA expression (Fig. 1B).


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  		Fig. 1.   A: effect of oncostatin M (OSM) on endothelin-1 (ET-1) production after 24-h incubation. Bars indicate SEs. *** P < 0.001 vs. control. B: effect of OSM on preproendothelin-1 (prepro-ET-1) mRNA expression after 4-h incubation detected by RNase protection assay. Gel bands were visualized by autoradiography and quantitated by densitometry. Bars are relative prepro-ET-1 mRNA levels normalized to beta -actin. Prepro-ET-1 mRNA gel bands (left to right) correspond to bars below.

IL-6 (10 ng/ml), which belongs to the same family of cytokines as OSM, also increased ET-1 production but appeared less potent than OSM (Fig. 2A).


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  		Fig. 2.   A: effect of interleukin (IL)-6 on ET-1 production. B: effect of anti-IL-6 on basal and OSM (10 ng/ml)-stimulated ET-1 production. Incubation time was 24 h. Bars indicate SE. Significant differences: ** P < 0.01, *** P < 0.001 vs. control; dagger dagger dagger P < 0.001 vs. OSM.

To study whether IL-6 was involved in OSM-induced ET-1 production, we treated endothelial cells with anti-IL-6. The stimulatory effect of OSM was reversed by anti-human IL-6 (33 µg/ml) (Fig. 2B), suggesting involvement of IL-6 in ET-1 stimulation. Also, basal ET-1 production was decreased by anti-IL-6 (33 µg/ml) (Fig. 2B). OSM caused no displacement of 125I-IL-6 bound to anti-IL-6, suggesting no cross-reaction between anti-human IL-6 and OSM.

The involvement of tyrosine kinase activation in OSM-induced ET-1 production was studied using tyrosine kinase inhibitors. The tyrosine kinase inhibitors herbimycin (250-500 ng/ml) and genistein (1-4 µg/ml) dose dependently decreased basal ET-1 production, whereas daidzein (1-8 µg/ml), a less active analog of genistein, was without effect (Fig. 3, A-C). The stimulatory effect of OSM was reversed by herbimycin (250 ng/ml) and genistein (2 µg/ml) but not by daidzein (2 µg/ml) (Fig. 4, A-C).


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  		Fig. 3.   Effect of herbimycin (A), genistein (B), and daidzein (C) on ET-1 production after 24-h incubation. Bars indicate SEs. ** P < 0.01, *** P < 0.001 vs. control.


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  		Fig. 4.   Effect of herbimycin (250 ng/ml) (A), genistein (2 µg/ml) (B), and daidzein (2 µg/ml) (C) on OSM (2.5 ng/ml)-stimulated ET-1 production after 24-h incubation. Herbimycin, genistein, and daidzein were added 15 min before OSM. Bars indicate SEs. Significant differences: ** P < 0.01, *** P < 0.001 vs. control; dagger  P < 0.05, dagger dagger P < 0.01, dagger dagger dagger P < 0.001 vs. OSM.

To study whether enhanced superoxide anion production by OSM was related to increased ET-1 production, we treated endothelial cells with SOD (20-200 U/ml), a scavenger of superoxide anion. However, SOD did not modify the stimulatory effect of OSM on ET-1 production (Fig. 5).


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  		Fig. 5.   Effect of superoxide dismutase (SOD; 200 U/ml) on basal and OSM (2.5 ng/ml)-stimulated ET-1 production after 24-h incubation. Bars indicate SEs. ** P < 0.01 vs. control.

The involvement of PKC in ET-1 regulation was studied. Activation of PKC with the phorbol ester PMA suppressed ET-1 production (Fig. 6A). Downregulation of PKC by PMA preincubation for 24 h potentiated OSM-induced ET-1 stimulation (Fig. 6B), suggesting that PKC activation has an inhibitory effect on OSM-mediated ET-1 release.


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  		Fig. 6.   Effect of protein kinase C downregulation on OSM-induced ET-1 production. Cell cultures were treated with OSM (2.5 ng/ml) or phorbol 12-myristate 13-acetate (PMA; 1 µM) for 24 h without (A) or with (B) PMA (1 µM) preincubation for 24 h. Bars indicate SEs. ** P < 0.01, *** P < 0.001 vs. control.

[3H]thymidine incorporation rates in confluent cell cultures were not changed by any of the test substances, thus excluding growth or toxic effects.

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

In the present study, stimulation of ET-1 production by OSM, a cytokine released by macrophages and T lymphocytes, was shown in human endothelial cell culture. OSM belongs to a family of IL-6-related cytokines and shares a structural and functional relationship with IL-6 (23). HUVEC express more high-affinity receptors for OSM than other cell types do (5). OSM has been reported to induce an increase in IL-6 production and IL-6 mRNA expression in human endothelial cells (5). OSM-stimulated ET-1 production was reversed by anti-human IL-6, suggesting that IL-6 was involved in OSM-stimulated ET-1 production. An increase of basal ET-1 production by exogenous IL-6 was also shown. However, for unknown reasons, IL-6 was less potent than OSM in stimulating ET-1. Geisterfer et al. (9) have reported that OSM stimulated IL-6 receptor mRNA expression in a rat hepatoma cell line, whereas IL-6 had little effect on the expression of its own receptor mRNA. Induced IL-6 receptor expression by OSM could possibly explain the potency of OSM.

Induction of tyrosine phosphorylation by OSM has been reported (26). To study whether tyrosine kinase activation was involved in OSM-induced ET-1 production, we treated HUVEC with the tyrosine kinase inhibitors herbimycin and genistein or with daidzein, a structural analog of genistein, which has only low tyrosine protein kinase inhibitor activity. Herbimycin and genistein attenuated basal and OSM-stimulated ET-1 production, whereas daidzein was less effective. These data suggest that tyrosine-phosphorylated proteins were involved in basal and OSM-stimulated ET-1 production. OSM-stimulated IL-6 production was reversed by genistein (26), which accords with the hypothesis that IL-6 is involved in OSM-induced ET-1 production.

Activation of tyrosine kinases can also lead to PKC activation (20). We studied whether PKC had a role in OSM-induced ET-1 production by downregulating PKC with PMA. Downregulation of PKC by PMA treatment potentiated OSM-induced ET-1 production. This suggests that PKC activated by OSM or by other substance(s) in cell culture had an inhibitory effect on OSM-stimulated ET-1 production. Activation of PKC by PMA suppressed basal ET-1 production, suggesting that PKC activation has an inhibitory effect on ET-1 production in HUVEC. Activation of PKC has been shown to decrease serum-stimulated ET-1 production in HUVEC (22).

OSM has been reported to enhance superoxide anion production in endothelial cells (18). Superoxide anions are able to inactivate endothelium-derived nitric oxide (10), which is probably an important physiological suppressor of ET-1 production (3, 25). Therefore, we studied whether superoxide anion production was involved in OSM-induced ET-1 production using SOD, a scavenger of superoxide anions. However, SOD treatment did not modify OSM-induced ET-1 production, suggesting that the possible superoxide anion induction by OSM was not involved in ET-1 stimulation.

Cytokines released by inflammatory cells may play a central role in vascular remodeling in association with atherosclerosis and hypertension. Cytokines have regulatory effects on vascular proliferation, migration, and contraction. OSM released by macrophages and activated T lymphocytes is a potent inhibitor of endothelial cell growth (27), whereas ET-1 is a growth-promoting factor (1) and an autocrine growth factor for endothelial cells (19). Interaction of OSM and ET-1 may be important in regulating vascular growth. It is of particular interest that OSM potently stimulates ET-1 production because OSM is released by inflammatory cells such as macrophages and activated T lymphocytes now considered important in the atherosclerotic process (24).

In conclusion, OSM stimulated ET-1 production in cultured human endothelial cells, an effect probably mediated by IL-6. Tyrosine kinase activation was involved in ET-1 stimulation. PKC activation seems to exert an inhibitory effect on basal and stimulated ET-1 production.

    ACKNOWLEDGEMENTS

This work was supported by grants from the Sigrid Jusélius Foundation (Helsinki), the Finnish-Norwegian Medical Foundation (Helsinki), the Aarne Koskelo Foundation, the Finnish Heart Association, the Liv och Hälsa Foundation, and Helsinki University Central Hospital Research Funds.

    FOOTNOTES

Address for reprint requests: O. Saijonmaa, Minerva Institute for Medical Research, Tukholmankatu 2, SF-00250 Helsinki, Finland.

Received 3 September 1997; accepted in final form 12 January 1998.

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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Am J Physiol Heart Circ Physiol 275(2):H662-H667
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society


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