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Previous Article | Next Article 
Clinical and Diagnostic Laboratory Immunology, July 2000, p. 553-556, Vol. 7, No. 4
1071-412X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Superantigens and Cystic Fibrosis: Resistance of
Presenting Cells to Dexamethasone
Josef
Ben-Ari,1,*
David
Gozal,1
Raymond J.
Dorio,2
C. Michael
Bowman,1
Andreas
Reiff,3 and
Sharyn M.
Walker2,4
Divisions of Pediatric
Pulmonology,1 Research Immunology/Bone
Marrow Transplantation,2 and
Rheumatology,3 Childrens Hospital Los
Angeles, and Department of Molecular Microbiology and
Immunology, University of Southern California School of
Medicine,4 Los Angeles, California
Received 10 December 1999/Returned for modification 25 January
2000/Accepted 24 March 2000
 |
ABSTRACT |
Staphylococcus aureus, a common pulmonary pathogen in
cystic fibrosis (CF), produces exotoxins that are extremely potent
superantigens. A number of animal studies have shown that superantigens
cause pulmonary inflammation, but the possible role of superantigens in
CF has not been investigated. The present study assessed possible differences between control and CF B cells in presenting superantigens to T cells. Immortalized B-cell lines were used as
superantigen-presenting cells to avoid environmental influences (e.g.,
infection or antibiotics) common to freshly isolated cells. The results
show that CF B-cell lines presented a staphylococcal superantigen to
the immortalized T-cell line (Jurkat) as effectively as did control
B-cell lines as measured by interleukin-2 production. However, in
contrast to the case for control B-cell lines, dexamethasone did not
inhibit CF B-cell lines from presenting superantigen. The resistance of superantigen-presenting CF B cells to corticosteroids suggests that the
pulmonary response to superantigens may be poorly regulated in CF,
leading to an exaggerated inflammatory response to S. aureus.
| |
INTRODUCTION |
Chronic bacterial infection of the
lung accounts for the majority of the mortality and morbidity observed
in cystic fibrosis (CF) (11, 17). Staphylococcus
aureus is frequently the initial colonizing microbe
(1). S. aureus is well known for production of a
family of exotoxins that are very potent activators of the immune
system (reviewed in reference 14). These exotoxins
are called superantigens, in part because they stimulate large numbers of T cells without a requirement for prior sensitization. The end
result is excessive production of T-cell and proinflammatory cytokines.
Staphylococcal superantigens are highly heat- and enzyme-resistant
proteins, notorious for causing food poisoning and toxic shock syndrome
(14). The possible role of staphylococcal superantigens in
pulmonary diseases has not received much attention until recently. Systemic or intratracheal administered superantigens elicit pulmonary inflammation in animals (12, 15, 22, 23). In addition, staphylococcal enterotoxins stimulate interleukin-8 (IL-8) production by cultures of bronchial epithelial cells (2) and by human lung microvascular endothelial cells (13). IL-8 is a
suspected major proinflammatory cytokine in CF (27).
The present study compared the ability of CF and normal B-cell lines to
present a staphylococcal superantigen to T cells. In addition, based on
a suspected abnormality of a number of CF cell types in regulation by
corticosteroids (6, 7, 18, 29, 32), including B cells
(10), the effect of dexamethasone on presentation of
superantigen by CF B-cell lines was also examined. Endogenous
corticosteroids and exogenous analogues, e.g., dexamethasone, are
potent inhibitors of proinflammatory cytokine production and inflammation (5, 30).
A simple assay system was employed, using the immortalized Jurkat
T-cell line as a source of T cells and immortalized control and CF B
cells as presenting cells (24, 33). B cells are one of
several cell types that can present superantigens (14, 24, 33), owing to their relatively high surface density of major histocompatibility complex (MHC) class II antigens. They also express
other surface substances, e.g., adhesion molecules, and produce
cytokines that facilitate T-cell stimulation (34). The use
of immortalized T- and B-cell lines to perform these studies avoided
possible extrinsic variables (antibiotic treatment or chronic infection
of patient, etc.).
| |
MATERIALS AND METHODS |
Culture medium.
RPMI 1640 (Irvine Scientific, Irvine,
Calif.) with HEPES buffer (10 mM), 10% heat-inactivated fetal calf
serum, penicillin (100 U/ml), streptomycin (100 µg/ml), gentamicin
(20 µg/ml), glutamine (2 mM), and 2-mercaptoethanol (5 × 10
5 M) was used.
Chemicals and cytokines.
Phorbol myristate acetate (PMA)
(Sigma, St. Louis, Mo.) was dissolved at 200 µg/ml in dimethyl
sulfoxide and stored at 
20°C. Staphylococcal enterotoxin E (SEE)
(Toxin Technology, Sarasota, Fla.) was dissolved in saline containing
0.1 mg of bovine serum albumin per ml to a stock concentration of 100 µg/ml. Further dilutions were made in culture medium. Dexamethasone
(LyphoMed Inc., Rosemont, Ill.) was dissolved in dimethyl sulfoxide and diluted in culture medium. Recombinant human interleukins were obtained
from Collaborative Research, Boston, Mass. (IL-1); Cetus Corp.,
Emeryville, Calif. (IL-2); Genzyme, Cambridge, Mass. (IL-4); and Amgen,
Thousand Oaks, Calif. (IL-6).
B-cell lines.
Epstein-Barr virus (EBV)-transformed B-cell
lines were established from the peripheral blood of children with and
without CF (31). Informed consent was obtained prior to
blood collection, and none of the children was on steroids. Control
B-cell lines were from age-matched children lacking known CF mutations.
All of the B-cell lines were homozygous for the delta 508 mutation except one line, CF-4, that had an unidentified mutation. In brief, to
establish the B-cell lines, lymphocytes were purified from heparinized
blood by density gradient centrifugation (33). The purified
lymphoid cells were cultured in 13-mm-diameter plastic tissue culture
tubes at 1 × 106 to 4 × 106/0.5 ml
of culture medium. EBV (5 × 107 transforming units)
(B95-8; Tampa Bay Research Institute, St. Petersburg, Fla.) and
cyclosporin A (1 µg/ml) were added. The B-cell lines were used at
least 2 months after transformation.
Superantigen presentation assay.
Jurkat T cells (clone E6-1,
TIB 152; American Type Culture Collection, Manassas, Va.) were cultured
with CF, and control B-cell lines with and without SEE added. The
Jurkat T-cell line does not produce IL-2 spontaneously but responds to
SEE presented by HLA-DR-bearing cells by producing IL-2 (24,
33). In brief, 5 × 104 Jurkat T cells and
2.5 × 103 B cells in 0.2 ml of culture medium
containing 6 ng of PMA per ml were added to flat-bottomed culture wells
of a 96-well plate (Falcon Plastics, Oxnard, Calif.). SEE was added at
a final concentration of 0.01 µg/ml. The number of B cells and
concentration of SEE used were determined by titration to be the lowest
required for optimal production of IL-2. After 24 h, supernatant
fluids were assayed for IL-2.
Stimulation of IL-6 production.
B-cell lines were cultured
in round-bottomed wells of a 96-well plate at 2 × 104
cells per well in 0.2 ml of medium. The cocktail used to stimulate IL-6
production was PMA (6 ng/ml) and recombinant cytokines IL-1 (40 ng/ml),
IL-2 (100 U/ml), and IL-4 (1 ng/ml).
Cytokine assays. (i) IL-2.
The murine T-cell line CTLL-2,
which is dependent on IL-2 for growth, was used for assay of
supernatant IL-2 as described previously (24, 33). One unit
of IL-2 was the dilution of supernatant that yielded one-half-maximal
proliferation relative to a standard curve. Results were expressed as
the mean ± standard deviation of three values. The assay
sensitivity was 0.1 U of IL-2/ml.
(ii) IL-6.
Il-6 was measured as described previously using
the murine IL-6-dependent hybridoma cell line B9.9 (16).
Polyclonal antiserum to IL-6 (Genzyme) neutralized the supernatant
activity. Results were expressed as the mean ± standard deviation
of three values. The assay sensitivity was 1 pg/ml.
| |
RESULTS |
Presentation of SEE by CF and control B-cell lines.
EBV-transformed CF and control B-cell lines were assessed for their
ability to present SEE to the Jurkat T-cell line, clone E6-1, which was
selected for high IL-2 production following activation (35).
In the presence of MHC class II-presenting cells, SEE is a potent
activator of Jurkat T cells, with other superantigens being
significantly less active (24, 33). IL-2 production is
greatly enhanced by the presence of PMA, a potent accessory signal for
T cells that have bound antigen or superantigens (34, 35).
The extent of activation of the Jurkat T cells is quantified by
measuring the IL-2 concentration in supernatant fluids approximately 1 day after activation (34, 35).
Table 1 shows the results of presentation
of SEE to the Jurkat line by CF and control B-cell lines. The B-cell
lines were effective presenters of SEE, with IL-2 production increased
from <1 to >10 U/ml in all cases except when presenting cells were omitted. There were no significant differences in IL-2 production (range, 11 and 15 U/ml) relative to the B-cell line used to present SEE. The B cells themselves made undetectable levels of IL-2, with the
Jurkat T cells being the sole source of IL-2 (data not shown).
It should be noted that to increase the likelihood of finding
differences between CF and control B-cell lines in presentation of SEE,
the lowest concentration of SEE and the fewest B cells that could
induce optimal IL-2 production by the T-cell line were used. The B-cell
number and concentration of SEE were varied in other experiments not
shown here, and, in all cases, CF B cells presented SEE to the Jurkat
T-cell line no differently than control B-cell lines.
Presentation of SEE after preincubation of B-cell lines with
dexamethsone.
Next, it was determined if there might be
differences in superantigen-presenting ability after preincubation of
the B-cell lines with corticosteroids. Corticosteroids are well-known
inhibitors of immune activity (5, 30), and a number of CF
cell types have been shown to be resistant to regulation by
corticosteroids (6, 7, 10, 18, 29, 32). Control and CF
B-cell lines were preincubated for 3 days with a range of
concentrations of dexamethasone, washed three times to remove
dexamethasone, counted, and then added to the T-cell line with and
without addition of SEE. After 24 h, supernatant fluids were
assayed for IL-2.
Figure 1 shows that treatment with
107 M dexamethasone inhibited control B-cell lines, but
not the CF B-cell lines, from presenting superantigen (58% ± 13%
[mean of two values] versus 6% ± 2% [mean of five values]).
These results are representative of those from three other experiments.
A concentration of 107 M dexamethasone was the highest
concentration that did not inhibit cell growth or reduce cell
viability; lower concentrations of dexamethasone were ineffective (data
not shown).
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|
FIG. 1.
Effect of dexamethasone pretreatment of B-cell lines on
subsequent presentation of SEE to the Jurkat T-cell line. CF and
control B-cell lines were preincubated with dexamethasone
(107 M) for 3 days. After three washes by centrifugation
to remove the dexamethasone, the B-cell lines were assessed for
superantigen presentation ability by addition to Jurkat T cells. SEE
was added at a final concentration of 0.01 µg/ml. After 24 h,
supernatant fluids were quantified for IL-2. Results are expressed as
the mean (± SD) percent inhibition of IL-2 production relative to IL-2
produced in response to SEE presented by non-dexamethasone-treated B
cells. The asterisks indicate no inhibition.
|
|
Mechanism of dexamethasone-mediated suppression of superantigen
presentation by control B-cell lines but not CF B-cell lines.
Because superantigens must bind to MHC class II molecules to be
presented, MHC class II expression on the dexamethasone-treated control
and CF B cells was compared. Fluorescence-activated cell sorter
analysis showed that dexamethasone had no effect on surface expression
of HLA class II molecules; no differences were detected between control
and CF B-cell lines with or without incubation with dexamethasone (data
not shown). The expression of another prerequisite surface molecule,
intracellular adhesion molecule 1 (ICAM-1) (34), also was
not affected (data not shown).
Because corticosteroids are known to inhibit proinflammatory cytokine
synthesis (5), it was next determined if dexamethasone affected the synthesis of IL-6 by the B-cell lines. The IL-6 gene has
corticosteroid response elements (25), and IL-6 is also made
by the B-cell lines in large amounts upon stimulation with a
PMA-cytokine cocktail, as shown in Table
2. Two of the five CF B-cell lines made
significantly more IL-6 than the others, but on the whole, control and
CF B cells made similar amounts of IL-6.
To study the effects of dexamethasone on IL-6 production, the B-cell
lines were first preincubated with dexamethasone for 3 days. The cells
were then washed three times, and the PMA-cytokine cocktail was added
to stimulate IL-6 production. Two days later the supernatant fluids
were assayed for IL-6. Figure 2 shows
that dexamethasone preincubation inhibited subsequent IL-6 production by the control B-cell lines but not the CF B-cell lines. The control B-cell lines were inhibited by 77% ± 15% (mean of 68, 99, and 65%),
while the CF B-cell lines were inhibited by only 4% ± 7% (mean of
17, 0, 4, 0 and 0%).
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[in a new window]
|
FIG. 2.
Effect of dexamethasone pretreatment on subsequent
stimulation of IL-6 production by CF and control B-cell lines. CF and
control B cell lines were preincubated with dexamethasone
(107 M) for 3 days. After three washes by centrifugation
to remove dexamethasone, the B cells were stimulated with and without a
cytokine-PMA cocktail (see Materials and Methods). Supernatant fluids
were quantified for IL-6 by bioassay. Results are presented as the mean
(± SD) percent inhibition of IL-6 production. The asterisks indicate
no inhibition.
|
|
| |
DISCUSSION |
Despite the fact that S. aureus produces the majority
of superantigens known, the possible role of superantigens in CF has not been studied. The present study found that CF B cells were resistant to inhibition of superantigen presentation by dexamethasone. If, as the present study suggests, the immune response to superantigens is poorly regulated in CF due to endogenous resistance to
corticosteroids, superantigens could play an important role in
pulmonary injury.
The mechanism of inhibition of the control B-cell lines with
dexamethasone was briefly examined. Inhibition was not explained by
cytotoxicity, as the concentration of dexamethasone used in these
studies was not cytotoxic. Possible down-regulation by dexamethasone of
surface molecules required for superantigen presentation, i.e., HLA-DR
and ICAM-1, was ruled out. Dexamethasone treatment was found, however,
to inhibit IL-6 production by control, but not CF B cells (Fig. 2),
suggesting that inhibition of IL-6 might be the mechanism of inhibition
of superantigen presentation. IL-6, however, is not required for the
Jurkat cells to produce IL-2 in response to SEE due to the presence of
PMA, which is itself a potent accessory signal for T cells (reference
35 and unpublished observation). Rather, these
preliminary mechanistic studies suggest that dexamethasone inhibits an
as-yet-unknown factor(s) that has corticosteroid response elements
(20, 25) similar to IL-6.
The mechanism for the resistance of the CF B-cell lines to regulation
by dexamethasone was not addressed in the present study. The
relationship between a defective CFTR gene product and an abnormal
response to corticosteroids remains speculative despite a number of
studies showing resistance of various CF cell types to corticosteroids;
these include freshly isolated B cells (10), bronchial
submucosal gland cultures (32), tracheal serous gland cultures (18), and fibroblasts (6). CF peripheral
blood lymphocytes are resistant to corticosteroid-induced inhibition of
arachidonic acid release (7) and leukotriene production
(29). On the other hand, the mitogen-stimulated
proliferation of peripheral blood control and CF T cells is equally
inhibited by corticosteroids (8, 21), showing that not all
CF cell types are resistant to corticosteroids. Because the CFTR gene
product not only is responsible for chloride ion transport but also
indirectly affects regulation of other ion channels (28), a
defective CFTR gene product could have a broader effect on cell
functions than chloride ion transport alone.
Although it is difficult to extrapolate from in vitro studies to
possible clinical significance, the abnormal response of many CF cell
types to corticosteroids suggests that corticosteroids may not be
effective in controlling inflammation in CF. In an early trial with
anti-inflammatory agents, long-term treatment with systemic
corticosteroids delayed progressive pulmonary deterioration (3); however, subsequent studies (9, 26) failed
to demonstrate a therapeutic response sufficient to justify the
significant side effects. Inhaled corticosteroids primarily benefited
patients with hyperreactive airways (4). A less toxic
anti-inflammatory treatment than corticosteroids, high-dose ibuprofen,
was shown to lower the rate of decline in pulmonary function in
children with CF compared to controls over a 4-year period
(19).
The use of immortalized T- and B-cell lines in the present study
facilitated detection of an intrinsic resistance of CF B cells to
dexamethasone. Immortalized cell lines are free of possible confounding
extrinsic variables, e.g., the clinical state of the patient, common to
freshly purified lymphoid cells. Moreover, CF B-cell lines provided a
pure population of B lymphoid cells, uncontaminated by other cell
types. The immortalized B-cell lines provide a convenient source of CF
cells for future molecular analysis of the relationship between the
defective CFTR gene product and corticosteroid regulation of
superantigen-presenting cells.
| |
ACKNOWLEDGMENTS |
This work was supported in part by a grant from the H. N. and Frances C. Berger Foundation and by the Southern California Chapter
of the Arthritis Foundation. Josef Ben-Ari is a recipient of an
American Physician Fellowship for Medicine in Israel, Inc., and David
Gozal is a recipient of a Parker B. Francis Fellowship in
Pulmonary Research.
| |
FOOTNOTES |
*
Corresponding author. Present address: Pediatric
Intensive Care Unit, Schneider Children's Medical Center of Israel, 14 Kaplan St., Petah Tikva 49202, Israel. Phone: 972-3-9253686. Fax:
972-3-9223004. E-mail: jbenari{at}clalit.org.il.
| |
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Clinical and Diagnostic Laboratory Immunology, July 2000, p. 553-556, Vol. 7, No. 4
1071-412X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
