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Infection and Immunity, July 1999, p. 3619-3624, Vol. 67, No. 7
Center for Vaccine Development, Departments
of Pediatrics and Medicine, University of Maryland, Baltimore,
Maryland 21201
Received 25 January 1999/Returned for modification 19 March
1999/Accepted 21 April 1999
The cytokine production patterns of human peripheral blood
mononuclear cells (PBMC) in response to Salmonella typhi
flagella (STF) were examined in culture supernatants of PBMC stimulated with STF. Consistent with previous findings in volunteers vaccinated with aroC aroD deletion mutants of S. typhi,
PBMC from volunteers immunized with the licensed live Ty21a S. typhi vaccine secreted gamma interferon following exposure to
STF. Stimulation with STF induced rapid de novo synthesis of tumor
necrosis factor alpha (TNF- The gram-negative bacterium
Salmonella typhi, a human host-restricted pathogen, is the
causative agent of typhoid fever (17, 18, 22). After
ingestion, S. typhi reaches the small intestine, where it
quickly penetrates the epithelium. A clinically asymptomatic incubation
period of 8 to 14 days ensues until clinical onset of typhoid fever,
characterized by symptoms that include fever and malaise and by a
sustained, low-level bacteremia (17, 18, 22). The mechanisms
leading to the bacteremia associated with the onset of typhoid fever,
which may include high bacterial load, bacterial virulence, and/or
host-mediated immune responses, are not well defined. Proinflammatory
cytokines, such as interleukin-1 Recently, it has been demonstrated that LPS is not the only
gram-negative bacterial constituent that elicits the production of
proinflammatory cytokines. The ability of Salmonella
typhimurium to elicit TNF- STF induction of cytokine production by human PBMC.
Peripheral
blood mononuclear cells (PBMC) were isolated and cultured as previously
described (32) from healthy naive volunteers or individuals
who had been immunized with the licensed Ty21a vaccine, an attenuated
flagellated S. typhi strain (Swiss Serum and Vaccine
Institute, Berne, Switzerland). PBMC were cultured for 4 days in the
absence or presence of S. typhi flagella (STF) or, as
controls, tetanus toxoid (TT) (Wyeth, Marietta, Pa.), bovine serum
albumin (BSA) (Fraction V; Sigma, St. Louis, Mo.), or the B-cell
epitope malarial multiple repeat of
asparagine-alanine-asparagine-proline (NANP50)
(Hoffman-La Roche, Basel, Switzerland [15]).
Supernatants were collected and the levels of IL-1
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Salmonella typhi Flagella Are Potent
Inducers of Proinflammatory Cytokine Secretion by Human
Monocytes
ABSTRACT
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Abstract
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References
) and interleukin-1
(IL-1),
followed by IL-6 and IL-10. Trypsin treatment of STF abrogated their
effects, while polymyxin B had no effect. Intracellular cytokine
measurements of STF-stimulated PBMC revealed the existence of monocyte
subpopulations that produce only TNF-, IL-1 or both cytokines.
Moreover, STF markedly decreased the percentage of CD14+
cells. These data demonstrate that STF are powerful monocyte activators
which may have important implications for vaccine development and for
understanding the pathogenesis of S. typhi infection.
TEXT
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Abstract
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References
(IL-1) and tumor necrosis factor
alpha (TNF-) have been shown to play an important role in the
development of fever and other symptoms associated with systemic
inflammatory response syndrome (SIRS) (1, 8). These
cytokines are released in response to gram-negative and other bacterial
infections (1, 31). Lipopolysaccharide (LPS), a constituent
of gram-negative bacterial cell walls, has been demonstrated to elicit
the production of IL-1, TNF-, IL-6, and other cytokines (8,
10, 16). High concentrations of LPS associated with high
bacteremia might lead to a severe form of SIRS referred to as endotoxic
shock (1, 8). It has been shown that IL-6, as well as the
proinflammatory cytokines IL-1 and TNF-, are involved in the
development of SIRS (1, 8). However, it is unlikely that
fever and other symptoms of typhoid fever are caused by LPS, since most
patients with typhoid do not exhibit increases in circulating levels of endotoxin and volunteers made LPS tolerant by repeated injections of
endotoxin developed typhoid fever when challenged with virulent S. typhi (17). Although levels of some cytokines,
such as IL-6, IL-8, and TNF-, appear to be elevated during acute
typhoid, the precise role of proinflammatory cytokines in induction
and/or perpetuation of fever and other symptoms during typhoid fever remains largely undefined.
production by human promonocytic
cell lines and peripheral blood adherent cells was shown to depend on
the expression of the fliC gene, which codes for flagella
(5, 6). Furthermore, purified S. typhimurium
porins were reported to cause human monocytes to produce TNF-,
IL-1, IL-1, IL-6, and gamma interferon (IFN-
) (11,
12), and S. typhimurium was shown to induce the
production of mRNA transcripts for granulocyte-macrophage
colony-stimulating factor (GM-CSF), IL-1, IL-6, macrophage
inflammatory protein 1 (MIP-1), and MIP-2 from mouse macrophages
(34). The increase in GM-CSF mRNA transcript production, but
not that of MIP-1, was dependent upon S. typhimurium
flagellum expression. No information concerning the effects of the
human pathogen S. typhi on human monocytes by bacterial
components other than LPS is available.
, TNF-, IL-10,
IFN-, and IL-4 were measured by chemiluminescence enzyme-linked
immunosorbent assay (ELISA) following standard procedures
(25). The sensitivity levels for the various cytokines
tested ranged from 0.2 to 2 pg/ml. Purified STF was prepared by a bulk
shearing method from the rough S. typhi strain Ty2R, as
previously described (29, 32). This STF preparation
consisted of a single flagellin band of ~55 kDa in sodium dodecyl
sulfate-polyacrylamide gel electrophoresis, formed a single strong
precipitate band with a rabbit anti-Ty2R flagellar antiserum in an
Ouchterlony, and contained less than 24 pg of LPS per ml, as determined
by using chromogenic Limulus amebocyte lysate kits (level of
sensitivity, 24 pg/ml) (Associates of Cape Cod, Inc.).
and TNF-
(Fig. 1A), as well as of IL-6 (data not
shown). Production of these cytokines was not observed in the presence
of the malarial antigen NANP, TT, or BSA (Fig. 1A). Elevated levels of
IFN- and IL-10, but not IL-4 (Fig. 1), were also induced by STF but
not by control antigens. Dose-response studies showed that following 24 h of exposure to antigen, production of both IL-1 and
TNF- was observed in PBMC cultures exposed to concentrations of STF as low as 4 ng/ml (data not shown). Experiments demonstrating that the
LPS inhibitor polymyxin B did not affect the ability of STF to induce
cytokine production (data not shown), as well as the demonstration that
trypsin digestion of STF abrogated its activity (data not shown),
confirmed that the induction of proinflammatory cytokines by STF was
not the result of LPS present in the STF preparation.
View larger version (25K):
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FIG. 1.
Induction of cytokine production by human PBMC after
exposure to STF. Cytokine production was measured in culture
supernatants 4 days after incubation in the absence (media) or presence
of STF (4 µg/ml), TT (2 µg/ml), the malarial repeat antigen NANP (4 µg/ml), or BSA (4 µg/ml). These results are representative of those
observed in 10 individual volunteers, all of whom were immunized orally
with the attenuated Ty21a S. typhi strain.
Time course of cytokine production after stimulation with STF by
PBMC isolated from naive volunteers or individuals immunized with the
Ty21a typhoid vaccine and requirement for de novo protein
synthesis.
To determine the earliest time at which cytokine
production induced by STF could be detected, PBMC from three volunteers
immunized with the Ty21a attenuated typhoid oral vaccine were cultured
in the absence or presence of STF or TT. Supernatants were collected at
5 min and at 1, 2, 4, 6, 24, and 48 h after addition of the antigen and examined for the presence of IL-1, TNF-, IL-10, and
IFN-. TNF- was the first cytokine to be detected in the supernatants of cultures stimulated with STF, appearing between 2 and
4 h after stimulation (Fig. 2A).
This was followed at 4 to 6 h by production of IL-1 (Fig. 2B).
IL-10 production could not be detected until 24 h after
stimulation (Fig. 2C). Similar to IL-10 production, IFN- secretion
was generally not seen until 24 h (Fig. 2D) and tended to have
higher variability among volunteers. This is consistent with IFN-
being a T-cell-derived cytokine, and the variability may reflect the
level of S. typhi Ty21a vaccine-induced priming in the
individual volunteers. Finally, it was observed that by 48 h,
production of TNF- began to decrease, IL-1 remained constant,
and, in contrast, both IFN- and IL-10 continued to increase (Fig. 2C
and D). Although the cellular origin of IL-10 was not determined,
IL-10, produced by cells of the monocyte/macrophage lineage and late in
antigen responses by T cells, is an important down-regulator of the
immune response (7). Thus, it is possible that late
production of IL-10 results in down-regulation of the high levels of
proinflammatory cytokines produced very quickly after exposure to STF.
|
could not be detected in
culture supernatants from immunized volunteers (Fig. 2), significant increases (P < 0.01) in the levels of IL-1 and
TNF- production were observed in both vaccinated and naive
individuals (data not shown). IFN- is known to be an activator of
cells from the monocyte/macrophage lineage that regulates production of
proinflammatory cytokines (8), and elevated levels of
IFN- in serum have been associated with febrile states (2, 14,
30). However, the possibility that IFN- production induced by
STF plays a significant role in the febrile state characteristic of
typhoid fever is unlikely, since the observation that IFN- does not
reach measurable levels in culture supernatants from immunized
volunteers during the first 24 h following exposure to STF rules
out the possibility that IFN- released by sensitized T lymphocytes
induces release of proinflammatory cytokines by monocytes/macrophages
in vitro. Moreover, the observation that volunteers immunized with the
licensed live oral Ty21a attenuated S. typhi strain also
secreted IFN-, but not IL-4, following exposure to STF confirms and
extends our previous observations on the immune responses elicited in
volunteers vaccinated with aroC aroD double deletion mutants
of S. typhi (28, 29).
To determine if the production of proinflammatory cytokines by STF was
due to the release of preformed cytokines or to de novo protein
synthesis, the protein synthesis inhibitors actinomycin D and
cycloheximide were added to PBMC cultures in the presence of STF, and
IL-1 and TNF- levels were measured in culture supernatants. We
observed that both inhibitors completely abrogated the ability of STF
to induce proinflammatory cytokines, indicating that de novo cytokine
production was required (data not shown).
Production of proinflammatory cytokines by monocyte cell
subsets.
The kinetics of the response and the ability of PBMC from
naive and vaccinated individuals to produce proinflammatory cytokines suggest an innate monocyte response. To study this phenomenon in more
detail, flow cytometric analysis was carried out to determine whether
all monocytes or a subset of these cells were involved in production of
proinflammatory cytokines and whether the same cells produce both
TNF- and IL-1. Intracellular cytokine content was determined by
flow cytometry as described previously (9, 20). Briefly,
following culture, cells were collected and stained for the surface
molecule CD14 by using an allophycocyanin-labeled anti-CD14 monoclonal
antibody (Caltag, Burlingame, Calif.), fixed with 4% formaldehyde,
permeabilized with 0.1% saponin, and stained intracellularly with
fluorescein isothiocyanate-labeled anti-IL-1 and
phycoerythrin-labeled anti-TNF- monoclonal antibodies (Pharmingen). Fluorochrome-labeled monoclonal antibodies of the same isotypes but
irrelevant specificities were used as controls. Data are presented as
two-color cytograms of IL-1 versus TNF- of cells gated on the
monocyte region (Fig. 3A). In agreement
with ELISA data, intracellular cytokine staining showed that by 5 h there was an induction of TNF- and IL-1 production in cells
stimulated with STF (Fig. 3). Of note, incubation with STF resulted in
a 50 to 70% decrease in the percentage of cells within the monocyte
region expressing CD14 (Fig. 3B) in STF cultures relative to those
incubated in the absence (media) or presence of TT (Fig. 3B). These
observations are in contrast to reports showing that incubation of
monocytes with LPS increases the level of CD14 expression
(21), thus indicating an important distinction between the
biological effects of LPS and STF. This reduction of CD14+
cells in the presence of STF might be the result of CD14 being modified
in such a way that it is no longer recognized by the anti-CD14
monoclonal antibody used in these studies, CD14 being internalized at
an accelerated rate or released into the supernatant as soluble CD14.
Experiments directed to explore these possibilities appear to rule out
the possibility that STF promotes the release of CD14 into the
supernatant. While exposure to LPS increased the levels of sCD14 in
culture supernatants, no increases in soluble CD14 were observed in
supernatants of cell cultures exposed to STF (33).
|
but not IL-1
(TNF-+ IL-1
cells) (26%) and in
IL-1+ TNF-+ cells (1.9%) (Fig. 3C). In
these cultures, IL-1 alone (TNF-
IL-1+ cells) was expressed in ~2% of the cells in the
monocyte region. In contrast, when stimulated with TT, only 1.4% of
the cells of the monocyte region were TNF-+
IL-1, while both TNF-
IL-1+ and TNF-+ IL-1+
double-positive cells were present in <1% of the cells. To enhance the detection of IL-1, whose release is not prevented by monensin, similar experiments were performed in the presence of methylamine (a
blocker of IL-1 secretion [26]). In the presence of
methylamine and monensin, a higher percentage of cells in the monocyte
region (~14%) became TNF-+ IL-1+ or
TNF- IL-1+, while ~28% of the cells
were TNF-+ IL-1 after exposure to STF
(Fig. 4). These percentages of
IL-1-containing cells were markedly higher than those observed in
cultures with monensin alone (Fig. 3), indicating that the addition of
methylamine resulted in an increase in our ability to identify
IL-1-producing cells. The fact that in the presence of both monensin
and methylamine large proportions of cells contained either one or both
cytokines suggests that different cell subsets might produce
predominantly either IL-1 or TNF-. Alternatively, these
observations might result, at least in part, from differences in the
kinetics of cytokine production by individual cells.
|
and TNF-,
as well as the anti-inflammatory cytokine IL-10, by PBMC from naive
volunteers or individuals immunized with the oral typhoid vaccine
Ty21a. Interleukin-1 and TNF-, which have been shown to play
major roles in the induction and persistence of fever (31),
were rapidly produced (within 6 h) by monocytes at high levels in
the presence of STF. These results are consistent with those showing
that S. typhimurium components other than LPS (e.g.,
flagellin and porins) are potent inducers of cytokine production in
vitro (5, 6, 11, 12, 34) and with the observations that
cytokines that are involved in the induction of fever, including IL-6,
IL-8, and TNF- as well as anti-inflammatory molecules such as
soluble TNF-R and IL-1R antagonist, are elevated during acute typhoid
(2, 19).
It has been proposed that TNF-, IL-1, and IL-6 production induced
by LPS from gram-negative bacteria causes fever and other symptoms
associated with SIRS in septic individuals (1, 8). Based on
our findings, we hypothesize that similar mechanisms might be
operational in SIRS associated with typhoid fever. In fact, the
observations that the production of high levels of IL-1, TNF-,
and IL-6 are elicited by STF, and likely other S. typhi components as well, suggest that in a gram-negative bacterium-infected septic individual more than one pathway to SIRS may be operating. Since
it is unlikely that fever and other symptoms observed during acute
typhoid are caused by LPS (17), it can be hypothesized that
organisms such as S. typhi, which persist in the
reticuloendothelial system, release bacterial components other than LPS
that might be able to induce SIRS without the release of LPS.
Alternatively, the combined release of LPS, STF, porins, and other,
as-yet-unidentified bacterial components may act in concert to trigger
the cascade of events that ultimately leads to SIRS. Many of the
efforts in the past to protect against SIRS have focused on interfering
with the binding of LPS to LPS-binding protein and/or to CD14 molecules on the surface of monocytes/macrophages (13, 24). However, the data presented in this paper, as well as results from other groups
(11, 12, 34), add further support for other strategies being
explored in the treatment of SIRS, such as the use of
anti-proinflammatory cytokines, inhibition of cytokine synthesis or
processing, specific IL-1R blockade with IL-1R blockade with IL-1R
antagonist, or administration of soluble cytokine receptors (8,
13).
Vaccines designed to elicit strong host immune responses to a defined
antigen(s) are currently under development. Among these are vaccines
utilizing bacterial vectors such as attenuated S. typhi
(4, 23) and STF carrying foreign antigens (27).
In conjunction with genes encoding foreign antigens, cytokine genes are
also being added to modify the response to the antigens in a desired,
protective way (3). It is therefore of critical importance
to fully understand the immune response to such vectors. The strong
proinflammatory response in the presence of STF demonstrated here
suggests that bacterial components of attenuated live vector vaccines,
such as S. typhi, may profoundly affect the immune responses to both the vector and the foreign antigen through the production of an
array of potent immunoregulatory cytokines. Further research into this
possibility will undoubtedly impact the design of future vaccines based
on live vector vaccines. We have described here an initial
characterization of the cytokine responses to only one of many
bacterial constituents that elicit immune responses. A complete
understanding of the human immune response to vaccination with
attenuated live vector vaccines will allow researchers to more
accurately predict the outcome of immunization with live vector
vaccines or combinations of antigens and cytokines.
| |
ACKNOWLEDGMENTS |
|---|
This work was supported by grant RO1 AI36525 from the National Institute of Allergy and Infectious Diseases, NIH.
We thank Myron M. Levine and Alan S. Cross for critical review of the manuscript. We also thank David Maneval for assistance in preparing the STF antigen.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Center for Vaccine Development, Departments of Pediatrics and Medicine, University of Maryland, 685 West Baltimore St., Rm. 480, Baltimore, MD 21201. Phone: (410) 706-2345. Fax: (410) 706-6205. E-mail: msztein{at}UMPPA1.ab.umd.edu.
Present address: SurroMed,Inc., Palo Alto, CA 94303.
Editor: J. R. McGhee
| |
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Infection and Immunity, July 1999, p. 3619-3624, Vol. 67, No. 7
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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