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Clinical and Diagnostic Laboratory Immunology, July 1999, p. 594-598, Vol. 6, No. 4
1071-412X/99/$04.00+0
Pentoxifylline Inhibits Superantigen-Induced Toxic
Shock and Cytokine Release
Teresa
Krakauer* and
Bradley G.
Stiles
Department of Immunology and Molecular
Biology, United States Army Medical Research Institute of Infectious
Diseases, Fort Detrick, Frederick, Maryland 21702-5011
Received 23 November 1998/Returned for modification 9 March
1999/Accepted 23 April 1999
 |
ABSTRACT |
Tumor necrosis factor alpha (TNF-
) is a critical cytokine that
mediates the toxic effects of bacterial superantigens like staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin 1 (TSST-1). Pentoxifylline, an anti-inflammatory agent that inhibits endotoxemia and lipopolysaccharide (LPS)-induced release of TNF-, was tested for its ability to inhibit SEB- and TSST-1-induced activation of human peripheral blood mononuclear cells (PBMCs) in vitro
and toxin-mediated shock in mice. Stimulation of PBMCs by SEB or TSST-1
was effectively blocked by pentoxifylline (10 mM), as evidenced by the
inhibition of TNF-, interleukin 1
(IL-1), gamma interferon
(IFN-
), and T-cell proliferation. The levels of TNF-, IL-1,
and IFN- in serum after an SEB or TSST-1 injection were
significantly lower in mice given pentoxifylline (5.5 mg/animal) versus
control mice. Additionally, pentoxifylline diminished the lethal
effects and temperature fluctuations elicited by SEB and TSST-1. Thus,
in addition to treating endotoxemias, the cumulative in vitro and in
vivo data suggest that pentoxifylline may also be useful in abrogating
the ill effects of staphylococcal enterotoxins and TSST-1.
| |
INTRODUCTION |
Staphylococcal exotoxins are among
the most common etiological agents that cause toxic shock syndrome
(2, 34). The disease is characterized by fever, hypotension,
desquamation of skin, and dysfunction of multiple organ systems
(6, 34). Staphylococcal toxic shock syndrome toxin 1 (TSST-1) and the distantly related enterotoxins are superantigens that
potently stimulate T-cell proliferation and cytokine production
(16). These toxins bind directly to the major
histocompatibility complex (MHC) class II molecules on
antigen-presenting cells and subsequently stimulate T cells that
express specific V elements on T-cell receptors (7, 16, 34,
35). In vitro and in vivo studies show that these superantigens
induce high levels of various proinflammatory mediators, including
tumor necrosis factor alpha (TNF-), interferon gamma (IFN-), and
interleukin 1 (IL-1) (14, 16, 17, 23, 27, 28, 36). These
cytokines upregulate the expression of MHC class II as well as adhesion
molecules and possess potent immunoenhancing properties
(18). Further evidence for the pivotal role of TNF- in
superantigen-induced shock was revealed by experiments with transgenic
knockout mice (3, 37) and neutralizing antibodies against
TNF- (22, 23).
Pentoxifylline is a methylxanthine derivative that inhibits the
production of TNF- by endotoxin-stimulated monocytes/macrophages at
the transcriptional level (11, 25) and is effective in reducing serum TNF- levels in mice with endotoxic shock
(32). Recently, pentoxifylline was reported to inhibit
adhesion and activation of human T cells (10). The drug has
been well characterized and subsequently used in clinical settings for
years with few deleterious side effects. This study was undertaken to
determine the effect of pentoxifylline on staphylococcal enterotoxin B
(SEB)- and TSST-1-induced cytokine production from human peripheral
blood mononuclear cells (PBMCs). The therapeutic efficacy of
pentoxifylline in superantigen-induced toxic shock was further examined
via an in vivo murine model (36).
| |
MATERIALS AND METHODS |
Reagents.
Purified SEB and TSST-1 were obtained from Toxin
Technology (Sarasota, Fla.). The endotoxin content of these
preparations was <1 ng of endotoxin/mg of protein, as determined by
the Limulus amoebocyte lysate assay (BioWhittaker,
Walkersville, Md.). Escherichia coli lipopolysaccharide
(LPS; O55:B5) was purchased from Difco Laboratories (Detroit, Mich.).
Human (h) recombinant (r) TNF-, peroxidase-conjugated anti-rabbit
immunoglobulin G (IgG) and peroxidase-conjugated anti-goat IgG were
obtained from Boehringer-Mannheim (Indianapolis, Ind.). Antibodies
against hTNF- were purchased from R&D Systems (Minneapolis, Minn.).
hrIL-1 was kindly provided by J. Oppenheim (National Cancer
Institute, Frederick, Md.). hrIFN- and antibodies against hIL-1
were obtained from Collaborative Research (Boston, Mass.).
Anti-hIFN- IgG, with and without biotin, were obtained from
Pharmingen (San Diego, Calif.). Mouse (m) rTNF, anti-mTNF- IgG,
mIFN-, and anti-mIFN- IgG were purchased from Biosource (Camarillo, Calif.). mrIL-1 and anti-mIL-1 IgG were obtained from
Genzyme (Boston, Mass.). Pentoxifylline and all other reagents were
from Sigma (St. Louis, Mo.).
Cell cultures.
Human PBMCs were isolated by Ficoll-Hypaque
density gradient centrifugation of heparinized blood from healthy human
donors. The PBMCs (106 cells/ml) were cultured at
37°C in 24-well plates containing RPMI 1640 medium and 10%
heat-inactivated fetal bovine serum. The cells were incubated with SEB
or TSST-1 (100 ng/ml) for 16 h, and the supernatants were
harvested and analyzed for TNF-, IL-1, and IFN- by an
enzyme-linked immunosorbent assay (ELISA) as described below.
Pentoxifylline, when present, was added simultaneously with the exotoxins.
Human T-cell proliferation assays.
PBMCs (105
cells/well) were plated in triplicate with SEB or TSST-1 (100 ng/ml),
with or without various concentrations of pentoxifylline, for 48 h
at 37°C in 96-well microtiter plates. The cells were pulsed with 1 µCi of [3H]thymidine (New England Nuclear, Boston,
Mass.) per well during the last 5 h of culture as described
previously (17). The cells were harvested onto glass fiber
filters, and the incorporated [3H]thymidine was measured
by liquid scintillation.
Murine model of superantigen-induced toxic shock.
Male
BALB/c mice (18 to 22 g; Harlan Sprague-Dawley, Frederick, Md.)
were kept in a pathogen-free environment. A sterile
temperature-identification transponder (IPTT-100; Biomedic Data
Systems, Maywood, N.J.) was implanted subcutaneously into each animal
and the temperature was monitored hourly (37) after an
initial intraperitoneal (i.p.) injection of SEB or TSST-1 (1 µg/mouse), followed 4 h later by an LPS injection (80 µg/mouse) as described previously (36, 44). Pentoxifylline
(5.5 mg/animal) was given i.p. at the designated time points.
Temperature data were calculated as the mean temperature reading ± standard deviation for each group (n = 5 mice per
group). The total number of mice dead versus alive was recorded at
72 h.
Sera were collected and pooled from each group (n = 5
mice per group and time point) at 6, 8, and 10 h after an i.p.
injection of SEB or TSST-1 (1 µg/animal). Pentoxifylline (5.5 mg/animal) was given 3 h after the toxin, and LPS was injected at
4 h. The levels of cytokines in sera were detected by ELISA as
described previously (36).
Cytokine detection.
The levels of hTNF-, hIL-1, and
hIFN- in culture supernatants from PBMCs or mTNF-, mIL-1, and
mIFN- in sera were measured via a sandwich ELISA by using
cytokine-specific antibodies, according to the manufacturer's
instructions (17, 36, 38). Recombinant cytokines (20 to
1,000 pg/ml) represented the standards for calibration, and the
detection limit of all assays was 20 pg/ml.
Statistical analysis.
The cytokine data were expressed as
the mean reading ± standard error of the mean and were then
subsequently analyzed for significant differences by Student's
t test with Stata (Stata Corp., College Station, Tex.).
Differences were considered significant if P was <0.05. The
2 test was used in the data analysis of the in vivo
protective effects of pentoxifylline. Differences between
pentoxifylline-treated and untreated control groups were considered
significant if P was <0.05.
| |
RESULTS |
Pentoxifylline inhibits SEB- and TSST-1-induced cytokines from
hPBMCs.
Previous in vitro studies indicate that pentoxifylline
prevents endotoxin-induced TNF- production by monocytes/macrophages (11). Since proinflammatory cytokines like TNF- play an
important role in superantigen-induced shock, the effect of
pentoxifylline was examined with hPBMCs incubated with SEB or TSST-1.
Figure 1 shows that pentoxifylline
effectively blocked in a dose-dependent manner the production of
TNF-, IL-1, and IFN- from PBMCs incubated with either toxin,
achieving total inhibition of all three mediators at 10 mM compared to
the level of inhibition for controls incubated with toxin alone
(P < 0.05). With 1 mM pentoxifylline, TNF- was inhibited by 100% in SEB-stimulated PBMCs and 78% in
TSST-1-stimulated cells. The levels of inhibition of IL-1 and
IFN- were 57 and 65%, respectively, for SEB-stimulated PBMCs and 99 and 55%, respectively, for TSST-1-stimulated cells. Lower
concentrations of pentoxifylline were not effective in blocking the
induction of these three cytokines in SEB-stimulated cells. However,
TNF- and IL-1 were reduced by 55% in TSST-1-stimulated PBMCs
with 0.1 mM pentoxifylline, whereas no inhibition of IFN- was
observed with this concentration.
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FIG. 1.
Inhibition of TNF- (A), IL-1 (B), and IFN- (C)
production by PBMCs stimulated with SEB
( ) or TSST-1
( ) alone or in the presence of
various concentrations of pentoxifylline. Values represent the
means ± standard deviations for duplicate samples from three
experiments.
|
|
Human T-cell proliferation due to SEB or TSST-1 is inhibited by
pentoxifylline.
In addition to increasing cytokine levels,
superantigens are also potent activators of T-cell proliferation.
Therefore, the effect of pentoxifylline on SEB- and TSST-1-induced
proliferation of T cells was examined next. The results show that
pentoxifylline significantly decreased superantigen-induced
proliferation of T cells in a dose-dependent manner, with maximal
inhibition (92 to 94%) achieved at the same concentration (10 mM) that
was most effective at blocking cytokine production (Fig.
2). The lack of proliferation or cytokine
release from PBMCs was not due to lethal effects of superantigen and
drug, as determined by trypan blue exclusion.
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FIG. 2.
Inhibition of T-cell proliferation in PBMCs stimulated
with SEB () or TSST-1
() by pentoxifylline. Values are the
means ± standard deviations for triplicate cultures and represent
data from three experiments.
|
|
Pentoxifylline attenuates serum cytokine levels in vivo.
On
the basis of the strong inhibitory effects of pentoxifylline on
superantigen-mediated cytokine production and T-cell proliferation in
vitro, the potential therapeutic role of pentoxifylline in vivo was
further investigated in mice. Previous studies (38, 44, 45)
optimized the doses of SEB, TSST-1, and LPS required for a murine model
of lethal toxic shock and accompanied temperature fluctuations recorded
within 12 h (37).
Elevated serum levels of TNF-
, IL-1
, and IFN-
are a prominent
feature of toxic shock mediated by superantigens (
22),
and
these results are clearly evident in a murine model (
36,
38,
44,
45). Therefore, the in vivo effect of pentoxifylline
on serum
cytokine concentrations was examined in mice injected
with SEB or
TSST-1. Peak levels of IL-1
, TNF-
, and IFN-
were
reduced by
40, 94, and 99%, respectively, in mice treated with
TSST-1, LPS, and
pentoxifylline compared with the levels in mice
treated with TSST-1
plus LPS but not pentoxifylline (Fig.
3).
The concentrations of the same cytokines in serum were inhibited
86%
(IL-1
) and 99% (TNF-
and IFN-
) in mice given SEB, LPS,
and
pentoxifylline compared to the concentrations in the sera
of mice
treated only with SEB plus LPS (Fig.
3). Pentoxifylline
also reduced
the serum TNF-
levels by 99% among controls treated
with
phosphate-buffered saline (PBS) and LPS but had no effect
on reducing
IL-1
concentrations.
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|
FIG. 3.
Peak levels of TNF- (A), IL-1 (B), and IFN- (C)
in mice treated with (i) SEB plus PBS, (ii) PBS plus LPS, (iii) PBS
plus LPS and pentoxifylline (PENTOX), (iv) SEB plus LPS, (v) SEB plus
LPS and pentoxifylline, (vi) TSST-1 plus LPS, or (vii) TSST-1 plus LPS
and pentoxifylline. Values represent the means ± standard
deviations for duplicate samples.
|
|
Pentoxifylline diminishes superantigen-mediated shock in mice.
Table 1 shows that pentoxifylline
significantly increased the survival rate among LPS-potentiated mice
previously injected with SEB or TSST-1. However, mice were not
protected if pentoxifylline was given 4.25 h after the SEB or
TSST-1 injection (data not shown). Additional data on temperature
fluctuations in LPS-potentiated mice injected with TSST-1 or SEB, with
and without pentoxifylline, were collected. Normally, there is a 6 to
9°C decrease in temperature within 12 h among mice injected with
1 µg of SEB or TSST-1 plus 80 µg of LPS (37). However,
relative to the temperature increases among controls treated with SEB
or TSST-1 plus LPS, there were less dramatic decreases in temperature
among pentoxifylline-treated animals (data not shown). The results of
protection against temperature fluctuations essentially paralleled the
lethality results.
| |
DISCUSSION |
Pentoxifylline has been used for many years to treat peripheral
vascular disease because it affects erythrocyte shape, platelets, and
plasma viscosity (8, 42). Further investigations showed that
the drug also potently affects endotoxin-induced release of TNF-, a
proinflammatory cytokine that plays an important role in
superantigen-mediated shock (22). The present study
demonstrated that pentoxifylline effectively inhibited
superantigen-mediated production of TNF-, IL-1, and IFN- by
human PBMCs in vitro. These results also mimic the human in vivo
responses of the drug against LPS stimulation (25).
Inhibition of these cytokines by pentoxifylline evidently occurs at the
transcriptional level and can last for up to 5 days after the final
pentoxifylline dose (11, 25). This extended protection may
be due to an upregulation of cytokine receptors that are shed from the
cell surface when the drug is no longer present. Besides decreasing the
levels of proinflammatory cytokines in vitro, superantigen-induced
proliferation of T cells was also completely blocked by pentoxifylline
in our study. This effect is likely a result of inactivation of
1 integrins on T lymphocytes, as suggested by a recent
study (10). Pentoxifylline also inhibits the expression of
activation markers CD25, CD69, and CD98 on T lymphocytes stimulated
with mitogens (10). Neutrophil functions such as adherence,
degranulation, and superoxide production induced by the inflammatory
cytokines TNF- and IL-1 are also blocked by pentoxifylline
(41). Thus, pentoxifylline has a broad spectrum of effects
and interferes with the activation of multiple cell types of the immune system.
Various reports on staphylococcal and streptococcal superantigens
indicate that bacterial endotoxin naturally potentiates the effects of
these toxins in vitro and in vivo (1, 4, 15, 21, 24, 27, 30, 33,
39, 40). Studies with rabbits reveal that intravenously
administered SEB releases lethal levels of endotoxin into the
circulatory system (29). Therefore, the use of
pentoxifylline, which has a proven ability to inhibit various
proinflammatory cytokines and reduce mortality associated with
endotoxemia, was a seemingly logical choice for our studies.
Previous studies with mice showed that pentoxifylline can be given
24 h before or up to 4 h after an LPS injection and still confer significant protection in a dose-dependent manner
(32). The same report reveals that increasing concentrations
of pentoxifylline also prevent the production of TNF from murine
macrophages incubated in vitro with LPS. We witnessed a similar dose
effect of pentoxifylline incubated with PBMCs and SEB or TSST-1. Our in
vivo studies also showed that pentoxifylline given up to 4 h after
an SEB or TSST-1 injection still afforded considerable protection
against mortality and temperature fluctuations. However, when the drug
was given 4.25 h after the toxin, which was only 15 min after
administration of the LPS dose, there was no protection in our toxic
shock model. These results revealed a finite time frame in which the
drug is efficacious. The lack of protection with pentoxifylline given after LPS administration suggests that the drug is extremely effective in abrogating the priming effect of SEB or TSST-1 on cytokine induction
in this murine toxic shock model. The serum cytokine and mortality data
reveal the protective effects of pentoxifylline following an injection
of SEB or TSST-1. Besides mice, pentoxifylline effectively prevents
LPS-induced mortality and diminishes serum TNF levels in rats
(26). Similar results were reported from studies with guinea
pigs (9), dogs (43), and chimpanzees (20), thus suggesting that this drug is efficacious in
various species.
Our in vivo studies showed that the beneficial effects of
pentoxifylline in superantigen-induced shock included increased survival, minimal temperature change, and a dramatic reduction in serum
TNF-, IL-1, and IFN- levels. Previous studies indicate a good
correlation between superantigen toxicity in mice and elevated levels
of these proinflammatory cytokines (36, 38, 44, 45). Recent
efforts in our laboratory with transgenic knockout mice further
emphasize the importance of TNF- and IFN- in superantigen-induced toxicity (37). Mice that lack IFN- or the p55 receptor
for TNF- are protected against superantigen-induced toxic shock
(3, 37). Additionally, the IL-10 molecule also plays a
protective role in our toxic shock model because transgenic mice that
lack IL-10 are more susceptible (i.e., die more rapidly) than wild-type animals (37). It has been reported that methylxanthines like pentoxifylline increase the release of IL-10 and TNF receptors into the
circulatory system of mice (13), thus possibly explaining the protective effects seen in our murine model of superantigen-induced shock. Studies by other investigators have also shown that antibodies against TNF- and IFN- protect mice against the lethal effects of
SEB or TSST-1 (3, 19, 22).
Various studies suggest that pentoxifylline may be useful in decreasing
the severity of bacterial infections. It has been reported in a rat
sepsis model that pentoxifylline diminishes the serum TNF- and IL-6
levels (31), which correlates well with the results of a
previous study with rats injected intravenously with endotoxin
(26). Pentoxifylline may also abrogate the potentially lethal sequelae associated with bacterial meningitis via inhibition of
TNF and IL-1 release from microglial cells (5). Finally, in
vivo studies with humans show that the release of IL-1, IL-6, IL-8,
and TNF- from PBMCs is downregulated after pentoxifylline treatment
(25).
In conclusion, the promising findings of this study indicate that
pentoxifylline has the potential to mitigate SE- and TSST-1-mediated shock in humans. Pentoxifylline protects mice against staphylococcal infections (41) and may be particularly useful among
patients suffering from severe infections due to the ever increasing
numbers of antibiotic-resistant bacteria (12) that produce
one or more toxic superantigens.
| |
ACKNOWLEDGMENTS |
We thank Robert M. Castle and Marilyn Buckley for excellent
technical assistance. The graphs were expertly done by Lorraine Farinick.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Immunology and Molecular Biology, Bldg. 1425, USAMRIID, Fort Detrick, Frederick MD 21702-5011. Phone: (301) 619-4733. Fax: (301) 619-2348. E-mail: terry_krakauer{at}detrick.army.mil.
| |
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Clinical and Diagnostic Laboratory Immunology, July 1999, p. 594-598, Vol. 6, No. 4
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Abstract
Introduction
