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Infection and Immunity, December 2000, p. 6663-6669, Vol. 68, No. 12
Department of Parasitology, Tulane Regional
Primate Research Center, Tulane University Health Sciences Center,
Covington, Louisiana
Received 19 June 2000/Returned for modification 7 August
2000/Accepted 28 August 2000
We determined previously that lipoproteins of Borrelia
burgdorferi stimulate inflammatory and anti-inflammatory
cytokines (interleukin-10 [IL-10]) in monocytes. IL-10 could have an
effect on innate and acquired immune responses to B. burgdorferi and influence the magnitude of the infectious
inoculum and disease outcome. To understand the mechanism(s) of IL-10
action during early infection, when innate immunity expressed chiefly
by skin macrophages is key, we investigated the effect of exogenous and endogenous IL-10 on the production of the macrophage-derived cytokines IL-6, IL-1 Borrelia burgdorferi, the
etiologic agent of Lyme disease, is spread to humans and other mammals
through the bite of infected Ixodes ticks (12).
The spirochete can invade multiple organs (5, 59) and
persist in them for a long time (46, 67). Spirochetal
persistence in the tissues has been associated with severe pathology
(15, 20, 67) and both acute and chronic inflammatory
conditions (50, 59). The mechanism(s) that drives the
infection to the various disease states is still not fully understood.
On the one hand, there is evidence that persistence of the spirochete
or its antigens in the tissues is required for pathology to ensue. On
the other, there is evidence that suggests that autoimmunity also may
play a part (29, 32, 58). It is now well documented that
B. burgdorferi lipoproteins can directly elicit inflammatory
responses both in vitro and in vivo (11, 26, 27, 47, 52, 57,
66). These results strongly support the paradigm that
pathogenesis of Lyme disease requires spirochetal persistence.
With the growing realization that cytokines play a key role in
inflammation, research on cytokine-mediated inflammatory reactions in
Lyme borreliosis is receiving great attention. Studies conducted to
date have revealed that B. burgdorferi and its lipoproteins can induce in a variety of cell types the release of proinflammatory cytokines such as interleukin-1 An important negative regulator of proinflammatory cytokines is the
anti-inflammatory cytokine IL-10 (44). IL-10 is secreted under different conditions of immune activation by a variety of cell
types, including T cells, B cells, and monocytes/macrophages (44). In vitro studies have shown that IL-10 suppresses the release and function of IL-1 It has been demonstrated that B. burgdorferi is capable of
inducing the production of IL-10 in vitro in mononuclear cells present
in peripheral blood (26, 31) and synovial fluid
(68). Yin et al. (68) also showed that IL-10 can
be produced concomitantly with Th1 cytokines when synovial fluid
mononuclear cells from infected patients are incubated with sonicated
proteins of B. burgdorferi. The same study showed that this
endogenously produced IL-10 can inhibit both
Borrelia-specific lymphocyte proliferation and TNF- We had hypothesized that IL-10 induced by B. burgdorferi
lipoproteins could contribute to the control of inflammation in Lyme disease, such that spirochetes would be endowed with a means of controlling the inflammation that they themselves are able to induce (26, 27, 49). The viability of this hypothesis was recently illustrated by Brown et al. (11). These
investigators demonstrated that C57BL/6J mice deficient in IL-10
(IL-10 IL-10 could have an effect on both the innate and acquired immune
responses to B. burgdorferi and could influence the
magnitude of the infectious inoculum as well as disease outcome. To
begin to understand the mechanism(s) of IL-10 action during the early phase of infection, when innate immunity expressed chiefly by skin
macrophages should play an important role, we investigated the effect
of both exogenous (added) and endogenous IL-10 on the production of the
macrophage-derived pro-inflammatory cytokines IL-6, IL-1 Bacteria and lipoproteins.
The JD1 strain of B. burgdorferi sensu stricto was used throughout. HBb were prepared
as previously described (26). HBb instead of viable
organisms were used in order to have a consistent batch of organisms
for all studies. Recombinant L-OspA and unlipidated OspA (U-OspA) were
the same as already reported (26, 27) and were obtained from
John Dunn, Brookhaven National Laboratories, Brookhaven, N.Y. The
L-OspA preparation contained less than 0.25 endotoxin unit per mg of
protein, as assessed by Limulus amebocyte assay (Associates
of Cape Cod, Woods Hole, Mass.). LPS from Escherichia coli
strain 026:B6 was from Sigma Chemical Company (St. Louis, Mo.).
Cell culture and stimulation of cytokine production.
The
THP-1 monocyte cell line was the same as described previously
(16) and was obtained from the American Type Culture
Collection (Manassas, Va.). THP-1 cells were pretreated with 0.05 µM
1 Effect of IL-10 on cytokine production.
To study the effect
of exogenous IL-10 on IL-1 Measurement of cytokine concentrations.
Cytokines were
measured as described previously (27). IL-6, IL-10, IL-12
(p40), and TNF- Kinetics of cytokine production.
For the study of kinetics
of cytokine production, cell-free supernatants were collected after
THP-1 cells had been stimulated for 1 h (TNF- Statistics.
Student's t test was used to compare
the data. Significance was established at a P level of 0.05.
Levels of cytokine production as a function of stimulant
concentration.
Experiments were first conducted to determine the
concentrations of L-OspA, HBb, and LPS required to stimulate THP-1
cells to produce detectable and optimal levels of IL-1
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Interleukin-10 Modulates Proinflammatory Cytokines
in the Human Monocytic Cell Line THP-1 Stimulated with
Borrelia burgdorferi Lipoproteins
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
, IL-12, and tumor necrosis factor alpha (TNF-
). We used the THP-1 human monocytic cell line and recombinant lipidated OspA
(L-OspA) as the model target cell and stimulant, respectively. To
determine the kinetics of cytokine production by THP-1 cells, we
stimulated them with L-OspA and also with heat-killed B. burgdorferi cells (HBb) and lipopolysaccharide (LPS). Exogenous
IL-10 dampened production of inflammatory cytokines, as elicited by
lipoproteins. The inhibition of endogenous IL-10 function by anti-IL-10
antibody reduced the production of IL-12 and IL-6 but not that of
IL-1 and TNF-. An inspection of the kinetics of cytokine
production clarified this finding. TNF- was produced prior to, and
IL- was produced at the same time as, IL-10, whereas IL-6 and IL-12 were produced later. HBb, LPS, and L-OspA yielded similar kinetics of
cytokine production. This result reinforces the notion that lipoproteins are the functional molecules in HBb and perhaps in vivo.
It indicates also that signaling pathways utilized by LPS and
lipoproteins may be extensively shared. The results are consistent with
a major role played by IL-10 in controlling the initial phase of
infection with this spirochete.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
(IL-1) (31, 35), IL-6
(2, 11, 30, 31, 43, 52, 60, 62), IL-12 (42), and
tumor necrosis factor alpha (TNF-) (11, 17, 31, 53).
These proinflammatory cytokines generally have potent effector
functions that overlap extensively with each other to bring about the
many components of inflammation, e.g., tissue necrosis (13,
64), chemotaxis of cellular infiltrates, induction of collagenase
and prostaglandin secretion by synovial fibroblasts and chondrocytes (16, 21), bone resorption, and cartilage destruction
(3, 63), as well as a plethora of microbicidal effector
mechanisms (48, 61).
, IL-6, TNF-, granulocyte-macrophage colony-stimulating factor, and IL-12 (14, 19, 23), thereby suggesting a normal endogenous feedback mechanism for the control of
immune responses and inflammation. Additionally, in vivo studies have
shown the direct suppressive effect of IL-10 on proinflammatory responses (4, 34, 41).
and
gamma interferon (IFN-
) production. Studies also have shown a novel
subset of T cells in human Lyme disease patients that secrete in vitro
both IL-10 and IFN- in the presence of exogenous IL-12
(51). Recently we showed that within the peripheral blood
mononuclear cell compartments of uninfected human and nonhuman primates, the cell type that transcribes the IL-10 gene in response to
heat-killed B. burgdorferi cells (HBb) is the monocyte. HBb can similarly induce an up-regulation of IL-1 and IL-6 (but not of
IL-4 and IFN-) transcription in these cells, as well as in the human
monocytic cell line THP-1 (27). This study also provided evidence that the monocyte produces both pro- and anti-inflammatory cytokines in response to purified lipoproteins of B. burgdorferi.
/) developed more severe arthritis yet harbored
10 times fewer spirochetes in the joints than wild-type C57BL/6J animals.
, IL-12, and
TNF-. We used the THP-1 human monocytic cell line and purified
recombinant lipidated OspA (L-OspA) as the model target cell and
stimulant, respectively. THP-1 cells were used to ensure consistent
results, as it is difficult to obtain the large quantities of human
peripheral blood monocytes that were required to conduct the
experiments presented in this paper. Although L-OspA appears not to be
expressed by B. burgdorferi in the early phases of infection
(6, 18, 50), the use of this (or any other) lipoprotein as a
model is justified in so far as its immunological effects are elicited
by the lipid, not the protein, moiety. The lipid moiety is likely
shared by all B. burgdorferi lipoproteins. We also
stimulated the THP-1 cells with lipopolysaccharide (LPS) and HBb. LPS
was used as a positive control for monocyte responses, and the B. burgdorferi cells were used to allow for inferences on whether
lipoproteins were the principal stimulants of monocytes/macrophages in
this spirochete. Finally, the kinetics of cytokine production by THP-1
cells upon stimulation with L-OspA, LPS, or HBb also was determined.
The results are discussed in terms of the possible role played by IL-10, as induced by B. burgdorferi lipoproteins, in
controlling the initial phase of infection with this spirochete.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
,25-dihydroxyvitamin D3 (Calbiochem-Nova Biochem
International, La Jolla, Calif.) for 48 h (36) prior to
being used in this study. For dose-response studies, THP-1 cells at
106/ml were stimulated with various concentrations of HBb
(105/ml to 108/ml) and L-OspA, U-OspA, and LPS
(0.01, 0.1, 1, and 10 µg/ml) for 48 h. Cultures were
subsequently centrifuged at 400 × g for 10 min at
4°C, and cell-free supernatants were collected and stored at 
70°C
until they were used.
, IL-6, IL-12 (p40), and TNF-
production, THP-1 cells were stimulated with 1 µg of L-OspA or LPS
per ml in the presence or absence of various concentrations (0.01, 0.1, 1, 10, and 100 ng/ml) of human recombinant IL-10 (rIL-10) (catalog no.
19701V; PharMingen, San Diego, Calif.). To determine the effect of
endogenous IL-10 on cytokine production, cells were stimulated with
L-OspA or LPS in the presence or absence of a neutralizing rat
anti-human IL-10 antibody (Ab) (catalog no. 18550D; PharMingen) at 10, 20, and 40 µg/ml. Normal rat immunoglobulin G1 (catalog no. 20610D)
(PharMingen) was used as control. All cultures were incubated for
48 h, after which time cell-free supernatants were collected
following centrifugation at 400 × g for 10 min at
4°C. Supernatants were aliquoted and stored at 70°C until they
were used.
(PharMingen) and IL-1 (Biosource International,
Camarillo, Calif.) in culture supernatants were measured by sandwich
enzyme-linked immunosorbent assay (ELISA) using paired
cytokine-specific monoclonal Abs according to the manufacturer's instructions.
) and 2, 8, 16, 24, 48, 72, 96, 120, 144, and 168 h. The concentrations of
stimulants used were 107/ml for HBb and 1 µg/ml for
L-OspA, U-OspA, and LPS.
RESULTS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
, IL-6, IL-12, TNF-, and IL-10. U-OspA and medium alone served as negative
controls. Cytokines were quantified in 48-h cultures using specific
ELISAs. L-OspA, HBb, and LPS induced cytokine production in a
dose-dependent manner. The concentrations of IL-1 and IL-6 were
augmented with increasing concentrations of L-OspA, HBb, and LPS (Fig.
1B and C). With the exception of L-OspA
at 10 µg/ml, IL-10 and IL-12 levels were also gradually augmented
with increasing concentrations of HBb and LPS (Fig. 1D and E). In
contrast, the concentration of TNF- decreased with increasing
concentrations of these stimulants (Fig. 1A). All cytokines except IL-6
were detectable at stimulant concentrations of 0.01 µg/ml, albeit at
low levels except for TNF-. This cytokine was produced at relatively
high levels (1,600 pg/ml) in response to a dose as low as 0.01 µg of
L-OspA or LPS per ml and 105 HBb per ml. HBb at
105/ml did not stimulate IL-1, IL-6, IL-12, or IL-10
production, a result previously observed by us for IL-6 and IL-10
(26). Neither U-OspA at any of the concentrations used nor
medium alone induced significant production of any cytokine. Based on
the results of this study, 1 µg of L-OspA, U-OspA, or LPS per ml and
107 HBb per ml were chosen as optimal concentrations for
stimulation of cytokine production in subsequent experiments.
View larger version (38K):
[in a new window]
FIG. 1.
Dose-response analysis of stimulants required to induce
optimal levels of TNF- , IL-1, IL-6, and IL-10 production. Vitamin
D3-treated THP-1 cells (106/ml) were incubated
for 48 h with supplemented medium (RPMI), various concentrations
of HBb (heat-killed spirochetes of the JD1 strain), L-OspA, U-OspA, and
LPS. TNF-, IL-1, IL-6, and IL-10 in the cell-free supernatants
were quantified by Ab capture ELISA. The lower limit of detection of
the ELISA was 15 pg/ml. Each bar represents the mean ± standard
deviation for duplicate cultures. Data are representative of those from
two separate experiments.
Effect of exogenous IL-10 on the concentrations of IL-12, IL-6,
IL-1, and TNF- induced by L-OspA and LPS stimulation.
We
examined whether exogenous IL-10 added at the time of stimulation was
able to affect the concentration of IL-, IL-6, IL-12, or TNF-
measured 48 h after L-OspA or LPS stimulation. This time point was
chosen because preliminary kinetic studies of cytokine production in
this system showed that at 48 h poststimulation (PS), cytokine
concentrations either had reached a plateau or were changing at a
relatively low rate. THP-1 cells were incubated with stimulants in the
absence or presence of rIL-10 at concentrations of 0.1, 1, 10, and 100 ng/ml. All tested cytokines were below the detection limits in the
absence of stimulants and in the presence of rIL-10 alone (data not
shown). IL-12 was significantly reduced (P < 0.007) in
supernatants of L-OspA-treated cells with as little as 0.1 ng of added
rIL-10 per ml and remained essentially undetectable at the higher
concentrations of added rIL-10 (Fig. 2).
Concentrations of IL-6 and TNF- also were significantly diminished
(P < 0.04) in the presence of all concentrations of
exogenous IL-10 (Fig. 2). IL-1 was not significantly reduced in the
presence of 0.1 ng of rIL-10 per ml but was significantly decreased
(P < 0.02) with 1 to 100 ng of added rIL-10 per ml
(Fig. 2). Our results indicate that exogenous IL-10 affects the
production (transcription, processing, and/or export) of inflammatory
cytokines by THP-1 cells when these cells are stimulated with L-OspA.
Similar results were obtained for each cytokine when LPS was used as
the stimulant (data not shown).
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Effect of endogenous IL-10 on the concentrations of IL-12, IL-6,
IL-1, and TNF- induced by L-OspA and LPS stimulation.
To
investigate if endogenously produced IL-10 could affect the
concentration of L-OspA- or LPS-induced inflammatory cytokines, neutralizing human anti-IL-10 Ab (10, 20, or 40 µg/ml) was added to
THP-1 cell cultures. The concentrations of all tested cytokines were
below the detection limits in the presence of anti-IL-10 alone (data
not shown). Anti-IL-10 Ab significantly affected (P < 0.01) the L-OspA-induced concentrations of IL-12 and IL-6 in an Ab
dose-dependent manner (Fig. 2). In contrast, concentrations of IL-1
and TNF- produced by L-OspA stimulation were essentially unchanged
at all Ab doses (P > 0.05) (Fig. 2). Similar results were obtained for each cytokine when LPS was used as the stimulant (not shown).
, and TNF-
production, using isotype-matched control Ab as well as other
appropriate controls. As already observed, 10 ng of rIL-10 per ml
markedly reduced the concentrations of IL-12, IL-6, IL-1, and
TNF- in L-OspA cultures. Additionally, anti-IL-10 Ab (20 µg/ml)
again failed to significantly enhance (P > 0.05) the
concentration of either IL-1 or TNF- but markedly enhanced the
concentrations of IL-12 and IL-6 as induced by L-OspA (data not shown).
Moreover, when both exogenous rIL-10 and anti-IL-10 Ab were added at
the same time to stimulated THP-1 cultures, the Ab completely
neutralized the inhibitory effect of rIL-10 on IL-6 and IL-1 levels
and partially (up to 78%) neutralized the effect on IL-12 and TNF-
levels. Isotype control Ab (20 µg/ml) did not affect the
concentration of any of the tested cytokines (data not shown).
Kinetics of IL-6, IL-1, TNF-, IL-10, and IL-12 production.
The kinetics of cytokine production by THP-1 cells was determined
using HBb, L-OspA, U-OspA, and LPS as stimulants. Cytokine concentrations were determined at 2, 8, 16, 24, 48, 72, 96, 120, 144, and 168 h after addition of the stimulants to the cultures. Neither U-OspA nor medium alone induced the production of any cytokines
at any time (data not shown). In preliminary experiments we had noticed
that TNF- was produced earlier than all other cytokines. Hence, this
cytokine was also quantified at 1 h PS. The concentrations of all
of the cytokines studied increased rapidly within the first 20 h
of stimulation with HBb, L-OspA, or LPS. After this time, cytokine
concentrations either continued to increase at a lesser rate (IL-6 and
IL-12), remained essentially constant (IL-1), or declined gradually
(IL-10 and TNF-). The concentration of TNF- was detectable within
1 h PS, reached its peak value at 2 h after this time, and
declined sharply thereafter. The concentration of IL-1 reached its
peak value between 10 and 20 h PS and was at roughly half that
value at about 2 h PS (Fig. 3). The
IL-10 concentration peaked between 8 and 16 h PS and declined
thereafter. The concentrations of both IL-6 and IL-12 increased more
slowly than those of the previous three cytokines and reached a plateau by 48 h PS.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The completion of the sequence of the B. burgdorferi genome has permitted new insights into the spirochete's immunobiology. The revelation that this organism has the potential of expressing more than 105 lipoprotein genes, roughly 11% of its genome's coding capacity (24), and the recent finding that lipoproteins can elicit not only inflammatory but also anti-inflammatory mediators, e.g., IL-10 from monocytes (27), have added support to the contention that lipoproteins are crucial virulence factors in Lyme disease pathogenesis.
IL-10, as elicited by lipoproteins from cells such as the macrophage,
may have an initial effect on the establishment of a B. burgdorferi infection, when innate immunity is at play, and a
subsequent effect on disease outcome, when acquired immune responses and perhaps even autoimmunity are the main protagonists. Here we have
focused on the effect of IL-10 on the macrophage response to
lipoproteins. We view this scenario as a model of the initial phase of
infection, when acquired immunity has not yet developed and when the
contribution of sensitized lymphocytes to the prevailing cytokine
pattern need not be factored in. Other cells of the innate immune
system also known to produce IL-10 in response to stimulants such as
LPS are Langerhans and dendritic cells. However, relative to
macrophages, a much lower proportion of these cells (0 to 5%) synthesizes IL-10 (as well as TNF-, IL-6, and IL-12) in response to
LPS (40) and thus possibly also in response to bacterial lipoproteins. Hence, the main source of "innate IL-10" in the initial phase of a B. burgdorferi infection in humans is
likely the monocyte/macrophage.
Our results show that IL-10 can significantly dampen the production (or enhance the uptake and binding) of inflammatory cytokines, as elicited from macrophages by lipoproteins. Although we have not formally demonstrated it in this paper, we will assume henceforth in this discussion that IL-10 influences the transcription, processing, and/or release (all grouped under the term production, for short), not the uptake and binding, of inflammatory cytokines by macrophages. This assumption is based on the parallelism we observed between the effects of L-OspA and LPS on cytokine concentrations measured at 48 h PS and as a function of time PS. In view of this parallelism and since IL-10, as induced by LPS, is known to affect the transcription, and hence the production, of inflammatory cytokines also elicited by LPS (19), our assumption is reasonable, notwithstanding the differences in LPS and lipoprotein receptors, i.e., Tlr4 for LPS (8) versus Tlr2 for lipoproteins (33, 39).
While production of the four proinflammatory cytokines we studied was
diminished by the addition of exogenous IL-10 to the cultures, the
inhibition of endogenous IL-10 function by added anti-IL-10 Ab seemed
to reduce production only of IL-12 and IL-6 and not of IL-1 and
TNF-. An inspection of the kinetics of cytokine production helps to
clarify this apparent contradiction. Both TNF- and IL- were
chiefly produced prior to (TNF-) or roughly at the same time as
(IL-) IL-10, whereas IL-6 and IL-12 were produced later. Hence, by
the time the endogenously produced IL-10 was available in the culture
medium for antibody binding, both TNF- and IL- already had been released.
Both the kinetic and dose-response attributes of TNF- production in
response to L-OspA, HBb, or LPS merit discussion. As already noted by
others, monocytes/macrophages produce TNF- shortly after stimulation
with either LPS (19) or lipoproteins (31). In our
study, the concentration of TNF- peaked within the first hour PS,
whereas those of all other cytokines, including IL-10, peaked or
reached a plateau at between 8 and 40 h PS. TNF- is a potent
neutrophil chemoattractant and inducer of phagocytosis and
cytotoxicity in both neutrophils and macrophages and thus plays a key
role in initiating and facilitating the innate immune response against
bacterial pathogens (1, 45). Even the reactivity of 
T
cells, a cell type which probably influences early innate host
responses, is triggered by TNF- (38). In view of this early and copious production of TNF-, our notion that B. burgdorferi lipoproteins facilitate the establishment of infection
by stimulating the production of IL-10 in macrophages would seem
ill-founded. However, the promotion of bactericidal effects is only one
aspect of the function of TNF-, for this cytokine is also essential in inducing the production of IL-10 by macrophages. In fact, TNF- has been shown to have a major enhancing effect on IL-10 mRNA production by monocytes. It induces a 20- to 120-fold increase over
baseline production. In contrast, IL-1, IL-1, IL-6,
granulocyte-macrophage colony-stimulating factor, transforming growth
factor , and IFN- have little effect (<3-fold). Moreover,
TNF- also augments LPS-induced IL-10 secretion (65).
Once again, it is possible that the same is true for
lipoprotein-induced TNF- and IL-10 production. Hence, if TNF- was
not secreted in the first place, the putative beneficial effects that
IL-10 may have on the establishment of a B. burgdorferi infection might be greatly diminished.
Another unique aspect of the kinetics of TNF- production was that,
unlike with the concentrations of the other cytokines we measured,
which either reached a plateau (IL-6, IL-12, and IL-) or decreased
very slowly thereafter, the concentration of TNF- decreased in a
biphasic fashion, swiftly between 1 and 45 h PS and more gradually
after that time. The apparent decrease in TNF- concentration may be
explained as follows. The THP-1 cell line can be induced to express and
release both TNF- receptors, TNF-R55 and TNF-R75, upon exposure to
LPS (28). Proteolytic cleavage of both receptors and release
of the corresponding TNF-binding proteins, TNF-R55-BP and TNF-R75-BP,
can be mediated by TNF- itself (7). TNF- is
functionally inactivated by TNF-R55-BP and TNF-R75-BP (6).
The apparent decrease in TNF- concentration may be due to its
binding to the soluble receptors. As a consequence, TNF- may have
failed to bind to either the capture or detecting Abs in the sandwich
ELISA that we employed for TNF- quantification.
Unlike with IL-1, IL-6, and IL-10, whose concentrations measured at
48 h PS increased in response to increasing concentrations of
stimulants, the concentration of TNF- diminished. The maximal concentration of TNF- was attained at the lowest concentration of
stimulants. In fact, the highest concentration of TNF- was observed
at a THP-1-to-spirochete cell ratio of 10:1 (Fig. 1A). One would
expect, as with the other cytokines, that TNF- transcription should
have been enhanced with increasing stimulant concentration, and most
likely this is what happened. However, since we measured the TNF-
concentration at 48 h PS, the putative effect of the release of
TNF-R55-BP and TNF-R75-BP must be taken into account as well. We submit
that, as the transcription of TNF- increased, in parallel with the
increase in stimulant concentration, the enhanced availability of
TNF- promoted the release of larger amounts of TNF-R55-BP and
TNF-R75-BP. As a consequence, less TNF- was detected in the medium
at 48 h PS.
Stimulation of THP-1 cells with HBb and L-OspA yielded similar kinetics of cytokine production. This further reinforces the notion that lipoproteins are the functionally active molecules in the HBb preparation and perhaps in vivo. Recently, it was shown that stimulation of monocytes by intact spirochetes occurs, as with pure lipoproteins, via CD14 (56). Hence, by inference, lipoproteins are the probable stimulants of monocytes/macrophages on live organisms. The responses to LPS and L-OspA that we observed also were notably analogous. This indicates that signaling pathways utilized by both stimulants may be extensively shared. It is already known that LPS and lipoproteins share CD14 as a coreceptor on cells of the myeloid lineage, while their respective receptors, namely T1r-4 and T1r-2, differ (8, 27, 33, 39, 47, 57, 66).
We have hypothesized here that IL-10, as elicited from macrophages by spirochetal lipoproteins, facilitates the establishment of a B. burgdorferi infection. To this end, IL-10 would contribute to down-regulate inflammatory and microbicidal effector mechanisms of the innate immune response. The observations we have made using THP-1 cells and L-OspA as a model are consistent with this notion. Interestingly, a similar role has been attributed to factors in tick saliva (10, 37, 54, 55). These factors, conveyed by the tick to the site of inoculation during spirochetal transmission, may act in synergy with spirochetal lipoproteins and usher spirochetes through the early localized phase of infection. Later, as the spirochetes disseminate and acquired immunity develops, both residual tick saliva- and lipoprotein-induced IL-10 may continue to influence the disease's natural history, by tilting the balance of the T-cell response towards a Th2 type (10, 22, 25, 37, 69) and, as posited by Brown et al. (11) and Giambartolomei et al. (26), by curbing inflammation.
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ACKNOWLEDGMENTS |
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We thank John Dunn (Brookhaven National Laboratory) for purified recombinant OspA. We also thank Christie Trew for her excellent secretarial help.
Special thanks go to the Department of Biotechnology, India, for providing a Senior Overseas Associateship to P. K. Murthy. This work was supported by grants U50/CCU606604 from the Centers for Disease Control and Prevention and RR00164 from the National Center for Research Resources, National Institutes of Health.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Parasitology, Tulane Regional Primate Research Center, 18703 Three Rivers Rd., Covington, LA 70433. Phone: (504) 871-6267. Fax: (504) 871-6390. E-mail: vida{at}tpc.tulane.edu.
Present address: Parasitology Division, Central Drug Research
Institute, Lucknow (U.P) 226001, India.
Editor: V. J. DiRita
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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