(Circulation. 1997;96:1501-1506.)
© 1997 American Heart Association, Inc.
Articles |
Modulation of Cytokine Production and Protection Against Lethal Endotoxemia by the Cardiac Glycoside Ouabain
From the Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan, and Hyogo Red Cross Blood Center (Y.N.).
Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp
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Abstract |
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Background Recent studies have shown that cytokines are capable of modulating cardiovascular function and that some drugs used in the treatment of heart failure variably modulate the production of cytokines. To examine whether cardiac glycosides also modulate cytokine production, we evaluated the effects of ouabain on the production of cytokines in vitro and in vivo.
Methods and Results Human peripheral blood
mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC
were cultured with or without ouabain in the presence or absence of
lipopolysaccharide (LPS). Ouabain induced the
production of interleukin (IL)-1ß, IL-6, and tumor necrosis
factor (TNF)-
in PBMC and induced mRNA of these cytokines,
an induction apparently at the transcriptional level. Amiloride,
staurosporin, and genistein inhibited cytokine
production, and protein kinase C and tyrosine kinase appeared
to be involved in the modulation of cytokine production
induced by ouabain. However, when PBMC were stimulated with LPS,
ouabain suppressed the production of IL-6 and TNF-. To
investigate whether ouabain modulates cytokine
production in vivo, we evaluated the effects of ouabain in
LPS-treated mice. Ouabain was found to protect against LPS-induced
lethal toxicity in mice and decreased circulating IL-6 and TNF-
levels in vivo.
Conclusions These previously unrecognized immunomodulating effects of a cardiac glycoside may explain either the beneficial or the detrimental effects of these drugs in heart failure patients.
Key Words: heart failure • interleukins • tumor necrosis factor • inotropic agents • shock
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Introduction |
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Since William Withering described the use of cardiac glycosides in his classic monograph on the pharmacology of the leaves of the common foxglove plant (Digitalis purpurea) in 1785,1 these agents have played a prominent role in the treatment of congestive heart failure. However, as long ago as the turn of the last century a controversy emerged regarding their efficacy and appropriate indications. The ability of digoxin to improve symptoms in patients with heart failure has been confirmed in two recently published withdrawal trials2 3 ; but, unlike vasodilators, the angiotensin-converting enzyme inhibitors, in particular cardiac glycosides, have not been shown to improve survival in patients with congestive heart failure, perhaps because the trials were too small to detect any but very large positive or negative effects on mortality. The results of the multicenter trial by the Digitalis Investigation Group, published recently, indicate that in a large population of patients with heart failure, long-term treatment with digoxin has no significant effect on overall mortality, though it reduced the overall rate of hospital admissions and that for worsening heart failure.4
Recently developed inotropic agents that increase the intracellular levels of cAMP, either by stimulating ß-adrenergic receptors or by inhibiting phosphodiesterase, have produced short-term hemodynamic improvements in patients with advanced heart failure. However, the results of long-term treatment with such agents have been mixed.
In our experimental model of congestive heart failure caused by viral myocarditis, vesnarinone improved survival and reduced myocardial damage, but survival was not improved by amrinone. These agents modulate natural killer cell activity in different ways.5 Furthermore, recent studies from our laboratory showed that drugs used to treat heart failure variably modulated the production of cytokines.6 7 8 Those experiments also suggested that some immunomodulatory effects of these drugs were pertinent to their effects in heart failure patients. This study was performed to investigate whether cardiac glycosides modulate cytokine production. Specifically, we evaluated the effects of ouabain on the production of cytokines in vitro and in vivo.
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Methods |
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Preparation of Human Peripheral Blood Mononuclear Cells
PBMC were obtained from healthy volunteers. PBMC were isolated by Ficoll-paque density centrifugation. The collected cells were washed three times with PBS, finally resuspended in RPMI 1640 medium (Gibco) supplemented with 10% heat-inactivated fetal calf serum (Gibco), 100 U/mL penicillin, 100 µg/mL streptomycin (Gibco), and 50 µmol/L 2-mercaptoethanol, and cultured at 37°C in a humidified 5% CO2 atmosphere.
Effects of Ouabain on the Production of Cytokines
by PBMC
Ouabain (Sigma) was dissolved in distilled water. After
incubation of the PBMC (2x106 cells/mL in 24-well plates,
n=6 wells, from 2 subjects) with ouabain for 24 hours, the supernatants
were harvested and stored at -80°C until cytokine assay.
IL-1ß, IL-6, and TNF- levels in the culture supernatants were
determined by specific ELISA kits (Otsuka Pharmaceutical Co).
To test the possible role of Na+/H+ or
Na+/Ca2+ exchanger in the induction of
cytokines by ouabain, PBMC were treated with amiloride, an
inhibitor of the Na+/H+ and
Na+/Ca2+ exchanger. Furthermore, the influence
of ouabain on the transcription of cytokine mRNA was examined
by measuring the production of cytokine in the presence
of actinomycin D, which inhibits transcription. Finally, the modulation
of ouabain-induced cytokine production by PK was
examined by exposing the media to the PK inhibitors
staurosporin and genistein. Amiloride, actinomycin D, staurosporin, and
genistein (Sigma) were dissolved in 0.1% DMSO and diluted with the
medium. This concentration of DMSO did not influence the
production of cytokine by PBMC. PBMC were incubated
with the agents in the presence of 10-7
mol/L ouabain for 24 hours, and supernatants were harvested for
IL-1ß, IL-6, and TNF- assay.
To investigate the effects of ouabain on the LPS-induced cytokine production, PBMC were stimulated with 1 µg/mL of LPS (Difco) immediately after administration of ouabain. After 24 hours of incubation the supernatants were harvested. Significant interindividual variability in cytokine production in response to LPS was observed. Therefore, we measured the cytokine production by PBMC from 3 subjects and in 2 wells from each individual.
Effects of Ouabain on mRNA Expression of IL-1ß, IL-6, and TNF-
of PBMC
These experiments were performed to study the effect of ouabain
on the induction of cytokine mRNA with the Northern blot
analysis method. PBMC were cultured as described above with or
without ouabain in the presence or absence of LPS and harvested 6 hours
after incubation. Total RNA was isolated by a guanidinium
thiocyanate/phenol/chloroform/isoamylalcohol procedure and
quantitated by spectrophotometry. To minimize variance in the yield of
RNA, each sample was pooled from three independent cultures. Ten
micrograms of total RNA was electrophoresed on a 1.2%
agarose-formaldehyde gel transferred to a nylon membrane (Gene Screen,
NEN Research Products) and successively hybridized with cDNA probes
for IL-1ß, IL-6, TNF-, and GAPDH. Recombinant cDNA clone obtained
from the American Type Culture Collection (Rockville, Md) was used to
prepare the DNA probe. Quantification of the RNA message was performed
with the use of a Fujix BAS 2000 image analyzer with
normalization to GAPDH message levels.
Effects of Ouabain on LPS-Treated Mice
The effects of ouabain on plasma IL-1ß, IL-6, and TNF-
levels were studied in 8-week-old female BALB/c, LPS-treated mice
(Shizuoka Agricultural Cooperation Association, Shizuoka, Japan). Each
animal received 1 mg/kg IP of ouabain immediately after the
injection of 250 µg of LPS. After 1, 2, or 4 hours, the mice were
bled by orbital puncture, and the plasma concentration of IL-1ß,
IL-6, and TNF- was determined by the ELISA method (6 mice per each
1-, 2-, or 4-hour period of time).
To study the effect of ouabain on LPS-induced lethal toxicity, 8-week-old female BALB/c mice each received 0.1 (n=20) or 1 (n=20) mg/kg IP of ouabain immediately after the injection of 250 µg IP of LPS.
Statistical Analysis
Statistical comparisons of cytokine production
were performed by ANOVA followed by Fisher's protected least
significant difference test for multiple samples comparison. The
comparison of the data on the effect of ouabain-induced
cytokine production by amiloride, actinomycin D, and PK
inhibitors was performed by Mann-Whitney U test
because the data included below-detectable levels. Kaplan-Meier plots
were made of the survival data, and survival differences between the
control and active treatment were tested by the Mantel-Cox log rank
test. Data are expressed as mean±SE. A value of P<.05 was
considered statistically significant.
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Results |
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Effects of Ouabain on the Production of Cytokines by PBMC
Ouabain caused a prominent increase in IL-1ß production in concentrations of 10-7 mol/L (29.0±3.0 versus 0.4±0.1 ng/mL at baseline, P<.01) and higher (Fig 1A
). In
contrast, induction of IL-6 and TNF- by ouabain occurred at a
concentration of 10-7 mol/L only, with
a small increase in its production from a baseline value of
0.7±0.2 ng/mL to a peak of 1.1±0.1 ng/mL and a
significant increase in TNF- from a baseline value of 0.3±0.1
ng/mL to a peak of 2.3±0.5 ng/mL (P<.01).
Exposure of the media to amiloride significantly inhibited the
ouabain-induced production of IL-1ß, IL-6, and TNF- (Table 1). Likewise, treatment of
PBMC with actinomycin D reduced the production of IL-1ß and
IL-6 and tended to decrease TNF- production (Table 1). A
variable modulation of cytokine production by PK
was observed. The PKC inhibitor staurosporin increased
production of IL-1ß and IL-6 in lower concentrations but
decreased their production in higher concentrations.
Staurosporin inhibited TNF- production in all concentrations
tested. The protein tyrosine kinase inhibitor genistein
increased the production of IL-1ß in lower concentrations and
inhibited it in higher concentrations, whereas the production
of both IL-6 and TNF- were inhibited in both concentrations (Table 2).
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Effects of Ouabain on the LPS-Induced Cytokine
Production by PBMC
Ouabain caused a concentration-dependent reduction in
LPS-stimulated IL-6 and TNF- release, a decrease that became
statistically significant at a concentration of
10-7 mol/L (Fig 1B
). In contrast,
ouabain enhanced IL-1ß production, which reached its peak at
10-7 mol/L (Fig 1B).
Effects of Ouabain on mRNA Expression of IL-1ß, IL-6, and TNF-
of PBMC
Exposure to 10-7 mol/L ouabain
markedly increased the accumulation of IL-1ß, IL-6, and TNF- mRNA
(Fig 2). At 6 hours, IL-1ß,
IL-6, and TNF- mRNA had increased by 4.6-fold, 3.2-fold, and
1.2-fold, respectively. LPS also increased the accumulation of IL-1ß,
IL-6, and TNF- mRNA. However, the induction of cytokine mRNA
by LPS was significantly inhibited in the presence of
10-6 mol/L ouabain.
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Effects of Ouabain on LPS-Treated Mice
In the absence of ouabain, LPS induced a rapid increase in
the plasma concentrations of IL-6 and TNF- within 1 hour. The
administration of 1 mg/kg ouabain immediately after injection of
LPS inhibited the increase in both (Fig 3). LPS induced only a
slight increase in the plasma IL-1ß (0.22±0.07, 0.26±0.04, and
0.38±0.09 ng/mL at 1, 2, and 4 hours, respectively), which was
not significantly inhibited by ouabain.
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At the dose of 250 µg per mouse, LPS caused death in 95% of
the animals within 48 hours. The administration of 1 mg/kg
ouabain immediately after administration of LPS significantly reduced
this mortality. This protective effect of ouabain, however, was dose
dependent and was not observed with the lower dose of 0.1 mg/kg
(Fig 4).
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Discussion |
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Ouabain and related cardiac glycosides are highly specific inhibitors of Na+/K+-ATPase. This enzyme (the sodium pump) catalyzes the coupled active transport of Na+/K+ across the plasma membranes of most animal cells.9 It is well established that the positive inotropic effect of a cardiac glycoside on the myocardium is due to the partial inhibition of the cardiac Na+/K+-ATPase, causing a small increase in intracellular Na+, which in turn affects the sarcolemmal Na+/Ca2+ exchanger, leading to an increase in intracellular Ca2+ and in the force of contraction.10 11 12 This effect on cardiac contractility is the basis for the main role of these drugs in the treatment of congestive heart failure.
Modulation of intracellular ion balance by Na+/K+-ATPase is an important mechanism by which cell growth and/or differentiation can be regulated. It has been reported that inhibition of Na+/K+-ATPase by ouabain can induce RNA encoding of the growth factors, IL-6, and macrophage colony–stimulating factor through what appears to be a calcium-dependent mechanism.13 14 Ouabain also has been shown to increase c-fos and c-jun transcription in a variety of cultured cells including myocytes.15 16 Induction of c-fos by ouabain appears to involve PKC, but the mechanism of PKC activation by ouabain has not been clarified. Previous studies have demonstrated that both inotropic and toxic concentrations of ouabain enhance phosphoinositide turnover, increase diacylglycerol content, and activate PKC.17 18 While these effects may be the consequence of activation of phospholipase C by ouabain-induced increases in intracellular Ca2+,17 there is also some evidence to suggest that activation of PKC by ouabain may occur by unidentified mechanisms independent of a ouabain-induced rise in intracellular Ca2+.18
In this study we found that the cardiac glycoside ouabain induced
production of IL-1ß, IL-6, and TNF- in human PBMC. Ouabain
induced mRNA of these cytokines, and the induction appeared to
be at the transcriptional level. Amiloride, staurosporin, and genistein
inhibited cytokine production. Therefore, PKC and
tyrosine kinase are thought to be involved in the modulation of
cytokine production induced by ouabain and to have
differential effects on the production of these
cytokines.
Sepsis and septic shock result primarily if not exclusively from
excessive stimulation of the host immune system, especially
macrophages, by the complex glycolipid (LPS, endotoxin), which
resides in the outer membrane of bacteria. LPS stimulates immunocytes,
mainly macrophages, to generate IL-1, IL-6, TNF-,
prostanoids, leukotrienes, and nitric oxide. Accordingly,
we studied the effects of ouabain on cytokine
production by LPS-stimulated PBMC. When PBMC were stimulated
with LPS, ouabain suppressed the production of IL-6 and
TNF-. Ouabain protected against LPS-induced lethal toxicity in mice
and decreased circulating IL-6 and TNF- levels in vivo. LPS
initiates signaling from the plasma membrane to the nucleus, which
involves activation of PKC, PKA, and the Na+/H+
exchanger19 20 and an increase in the number of
K+ channels,21 though the signal transduction
pathways are not completely understood. Furthermore, the mechanism of
modulation of LPS-induced IL-1ß, IL-6, and TNF- production
by ouabain is not clear, although these findings suggest that ouabain
may variably regulate the production of these
cytokines.
The dosages of ouabain used in murine experiments are higher than the dosages that are currently used to treat heart failure patients. It is difficult to compare dosages in different animal species; however, on the basis of body surface area, a given dosage in mice is comparable with a dosage about 12-fold lower in humans.22 Thus, a dosage of 1 mg/kg in mice is equivalent to 0.08 mg/kg in humans.
A growing body of literature suggests that cytokines are
capable of modulating cardiovascular
function.23 Concentrations of TNF- are increased in
patients with chronic heart failure,24 25 and TNF- has
been reported to depress myocardial
contractility.26 27 28 Although the effect of
IL-1 on cardiac function is controversial, IL-1 has also been
demonstrated to decrease cardiac
contractility.29 30 31 Furthermore, IL-1ß,
TNF-, and interferon-
have cytotoxic effects on cultured cardiac
myocytes.32 In addition to these humoral effects, these
cytokines may activate cytotoxic T cells, which may
cause direct injury to myocytes.33 More recently, IL-1ß
has been shown to cause myocyte hypertrophy associated with
induction of fetal genes.34 IL-6 may exert a negative
inotropic effect,26 and mice overexpressing both IL-6 and
IL-6 receptors have been found to develop cardiac
hypertrophy.35
Recent observations suggest that growth abnormalities that accompany
hypertrophy of the overloaded myocardium may
play an important role in the deterioration of the condition of
patients with chronic heart failure.36 As IL-1 and IL-6
may play important roles in the development of cardiac
hypertrophy,34 35 these cytokines may
be involved in potentially important maladaptive mechanisms that
develop in advanced heart failure. In the present study, ouabain
induced the production of IL-6 and TNF- but suppressed their
induction in a stimulated condition in vitro. Furthermore, ouabain
inhibited the production of IL-6 and TNF- in a murine model
of endotoxemia in vivo. Thus, ouabain may have different effects on
cytokine production in the unstimulated condition and
in the immunologically activated state. It is difficult to
compare the effects of drugs among different species, but it is
important to note that variable effects of ouabain on the
production of cytokines were seen in vitro and in
vivo.
Studies similar to those reported here need to be performed in humans, given the significant differences in some of the responses of animals and of humans. Assuming that the present findings can be extrapolated to patients with congestive heart failure, digitalis glycosides may have different effects on the production of cytokines among those with and those without immune activation. Until the nature of these previously unrecognized effects of cardiac glycosides is clarified, however, whether the modulation of cytokine production is a part of the beneficial or of the undesirable effects of these drugs in heart failure patients will remain uncertain. These questions may be pertinent to the current efforts aiming at reassessing the value of cardiac glycosides and related drugs in the treatment of heart failure.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a Research Grant from the Japanese Ministry of Health and Welfare and a Grant-in-Aid for General Scientific Research from the Japanese Ministry of Education, Science, and Culture. We would like to thank Y. Ohmoto and H. Toriyama for their assistance in the assay of cytokines, Dr T. Kitayoshi for his valuable advice, Dr A. Schwarz for critical reading of the manuscript, and T. Nakano and S. Sakai for preparing the manuscript.
Received January 29, 1997; revision received March 25, 1997; accepted April 8, 1997.
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