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*
Istituto di Microbiologia, Facoltà di Medicina e Chirurgia, Università degli Studi di Messina, Messina, Italy; and
Institute for Cancer Research, University of Trondheim, Trondheim, Norway
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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was measured in culture supernatants after
stimulation with whole heat-killed bacteria. Human serum and
anti-CD14 Abs significantly increased and decreased, respectively,
TNF- responses to the Gram-negative Escherichia coli.
However, neither treatment influenced responses to any of the
Gram-positive bacteria tested, including group A and B streptococci,
Listeria monocytogenes, and Staphylococcus
aureus. Complement receptor type III (CR3 or CD18/CD11b) Abs
prevented TNF- release induced by heat-killed group A or B
streptococci. In contrast, the same Abs had no effects when monocytes
were stimulated with L. monocytogenes or S.
aureus. Using either of the latter bacteria, significant
inhibition of TNF- release was produced by Abs to CD11c, one of the
subunits of CR4. To confirm these blocking Ab data, IL-6 release was
measured in CR3-, CR4-, or CD14-transfected Chinese hamster ovary cells
after bacterial stimulation. Accordingly, streptococci triggered
moderate IL-6 production (p < 0.05) in CR3 but not
CD14 or CR4 transfectants. In contrast, L. monocytogenes
and S. aureus induced IL-6 release in CR4 but not CR3 or
CD14 transfectants. Collectively our data indicate that
ß2 integrins, such as CR3 and CR4, may be involved in
cytokine responses to Gram-positive bacteria. Moreover, CD14 may play a
more important role in responses to whole Gram-negative bacteria
relative to Gram-positive ones. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Less is known of cell activation mechanisms initiated by whole bacteria relative to the many studies conducted with the LPS component of the Gram-negative cell wall. Monocyte activation triggered by LPS involves binding to CD14, a GPI-anchored protein lacking an intracytoplasmic portion (5, 6, 7). Binding of LPS to CD14 is greatly increased by serum LPS-binding protein, which may account for the ability of serum to enhance LPS responses (6, 8). Host cell receptors capable of transducing signals originated by Gram-positive bacteria, which are devoid of LPS, have been only recently investigated. Similar to LPS, peptidoglycan, a component of both Gram-positive and Gram-negative bacteria, and lipoteichoic acids, present in the membrane of Gram-positive bacteria, appear to activate cells through CD14-dependent mechanisms (9, 10, 11, 12, 13).
Complement receptor type III (CR3),3 a ß2 integrin formed by noncovalently linked CD18/CD11b complexes, can bind, in a complement-independent fashion, a number of protozoal, bacterial, and fungal components (14, 15, 16, 17, 18). CR3 can also bind to LBP (19), and, in the presence of serum and LPS, associate transiently with surface CD14 on the plane of the neutrophil membrane (20). CR4, also a ß2 integrin, is made up by CD18/CD11c and may be involved in transducing LPS signals in the absence of serum (21). Recent studies indicate that some human homologues of the Drosophila melanogaster Toll proteins, known as Toll-like receptor (TLR) 2 and TLR4, can function as LPS signal transducers (22, 23).
The present study was undertaken to identify monocyte receptors involved in cytokine responses to whole bacterial cells, focusing particularly on different Gram-positive bacteria. Our data indicate that ß2 integrins may play a role in responses to whole Gram-positive bacteria. Moreover, cytokine responses to the latter may be less CD14 dependent than those to Gram-negative bacteria or soluble products from both types of bacteria.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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COH-1, an encapsulated type III Streptococcus agalactiae (group B streptococcus or GBS) strain, was kindly provided by Craig Rubens, University of Washington, Seattle. Streptococcus pyogenes (group A streptococcus or GAS), Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli were recent clinical isolates. All of these bacteria were grown to the early stationary phase in Todd-Hewitt broth and harvested by centrifugation. Killed bacteria were prepared by heat-treatment (60°C for 45 min), followed by extensive washing with distilled water and lyophilization.
Reagents
The following mAbs (all mouse IgG1) were purified by G protein (GammaBind G Sepharose; Pharmacia Biotech, Milan, Italy) affinity chromatography (24) from culture supernatants of the following hybridomas purchased from the American Type Culture Collection (Manassas, VA): TS1/18 (anti-human CD18); LM-2/1.6 (anti-human CD11b); HB 247 (anti-human CD14). Anti-human CD11c mAb was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Mouse IgG1, used as a control, LPS from Salmonella enteriditis, and polymixin B were obtained from Sigma Chimica (Milan, Italy).
Monocyte cultures
Mononuclear cells were obtained from the peripheral blood of
healthy adult donors by centrifugation on Ficoll-Hypaque (Pharmacia)
(25). Cells at the interface were extensively washed and
resuspended to a concentration of 2.5 x
106/ml in RPMI 1640 supplemented with
streptomycin (50 µg/ml), benzylpenicillin (50 IU/ml), and 10 mM
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic
acid (Life Technologies, Milan, Italy). Then 200 µl of the cell
suspension were dispensed to the wells of microtiter plates and
incubated for 2 h in a 5% CO2 humidified
atmosphere at 37°C. Thereafter, nonadherent cells were aspirated and
adherent monocytes were washed twice in RPMI 1640. Monolayers were
incubated with mouse IgG1 or mAbs at the indicated concentration for 30
min at 37°C, before the addition of the stimuli. After a 4-h
incubation, culture supernatants were collected and stored at -70°C
until assayed for TNF- measurement. At the end of the experiments,
cell viability, as determined by trypan blue exclusion, was always
>90%. To study the effects of serum components, in some experiments
monocytes were cultured with the stimuli in the presence of 10%
heat-inactivated (56°C for 30 min) FCS (Fetalclone I, HyClone
Laboratories distributed by Celbio, Milan, Italy) or human serum
obtained from healthy volunteers. Human sera were devoid of Abs against
the Gram-positive bacteria tested, as assessed by ELISA (26, 27). In the latter test, 1 x 106
killed bacteria per well were used as sensitizing Ags. Human sera
producing absorbance values 
0.2 at 405 nm using a 1:200 serum
dilution were considered negative.
TNF- measurement
TNF- measurement was performed with a cytotoxicity assay
using TNF--sensitive WEHI 164 clone 13 cells (28, 29).
Ten serial 2-fold dilutions (from 1:4 to 1:2048) were tested in
duplicate for each sample. The assay was calibrated with human
recombinant TNF- (sp. act., 20 U/ng; Genzyme, Cinisello Balsamo,
Italy) as a standard. TNF- concentrations were determined by
comparing the cytotoxic activity of each sample with that of the
standard using a standard curve generated by linear regression
analysis. TNF- activity in selected plasma samples was totally
inhibited by a 1:100 dilution of anti-human TNF- rabbit serum
(Genzyme), but not normal rabbit serum. Because bioassays, such as the
one described, may underestimate the amounts of cytokine produced
because of the possible coinduction of soluble receptors, TNF- was
also measured, in selected supernatants, using a commercial immunoassay
with a sensitivity of 5 pg/ml (Cytoscreen hTNF- ELISA kit, BioSource
International, distributed by Celbio). For this purpose, 12 samples
from four separate experiments were tested. The immunoassay showed a
strong correlation with the bioassay.
Transfected cells lines
Chinese hamster ovary (CHO) cells transfectants expressing CD14, CR3, CR4, or CD14/CR3 and CD14/CR4 combinations and CHO/NEO control cell (30, 31, 32) were a kind gift of Dr. Golenbock (Boston University, Boston, MA). Transfectants were maintained in RPMI 1640 medium supplemented with 10% FCS and 1 mg/ml of G418 (Life Technologies) in a 5% CO2 humidified atmosphere at 37°C. CHO cells were incubated for 4 h with the bacterial stimuli at the indicated concentrations. Culture supernatants were then harvested and stored at -70°C until assayed for IL-6 concentration. None of the tranfectants used in the present study produced detectable IL-6 in the absence of stimuli.
IL-6 was measured using the IL-6-dependent 7TD1 cell proliferation assay, as described (33). One unit of IL-6 was defined as the amount that induced 50% maximal proliferation. The assay was calibrated using recombinant murine IL-6 (1 x 108 U/mg; Boehringer Mannheim, Milan, Italy) as a standard. The detection limit of the assay was 1 U of IL-6. IL-6 concentrations were determined by comparing absorbance values of each sample with those of the standard using a standard curve generated by linear regression analysis.
Data expression statistical analysis
Cytokine levels were expressed as means ± SDs of three independent observations, each conducted on duplicate samples. Differences in cytokine levels were assessed by one-way ANOVA and Student-Newman-Keuls test. Differences were considered significant at values of p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the absence of bacterial stimuli, TNF- levels of monocyte
culture supernatants were below the detection levels of either the
cytotoxicity or immune assays. To determine whether CD14, CR3
(CD18/CD11b), or CR4 (CD18/CD11c) are involved in TNF- responses to
whole bacteria, monocytes were pretreated with anti-CD14,
anti-CD18, anti-CD11b, or anti-CD11c mAbs before the
addition of killed bacteria. In preliminary experiments, spontaneous or
bacteria-induced TNF- production was not affected by monocyte
pretreatment with up to 100 µg/ml of control mouse IgG1 (not
shown).
Moreover, in the absence of bacteria, monocytes did not produce
detectable TNF- after the addition of anti-CD14, anti-CD18,
or anti-CD11c Abs at concentrations of up to 100 µg/ml (not
shown). Anti-CD11b at concentrations of 10 µg/ml or higher produced,
in the absence of other stimuli, TNF- elevations that never exceeded
6% of maximal, LPS-induced stimulation (not shown). These slight
TNF- responses were not inhibited by polymixin B (15 µg/ml),
ruling out endotoxin contamination of the Ab preparation.
Figs. 1
–3
show the effects of anti-receptor Abs on TNF- responses to 50
µg/ml of killed bacteria (dry weight of lyophilized cells).
Experiments were conducted both in the absence and in the presence of
10% heat-inactivated FCS. Fig. 1 shows that serum markedly increased
the TNF- response to E. coli (upper panels).
Anti-CD14 markedly reduced (p < 0.05) E.
coli-induced stimulation both in the absence and in the presence
of serum. Anti-CD18 or anti-CD11b produced moderate, but
significant (p < 0.05), inhibition in the
presence, but not in the absence, of serum. Conversely, anti-CD11c
significantly decreased TNF- responses to E. coli in
serum-free conditions only.
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, lower panels) generally paralleled those observed with
E. coli. In fact, anti-CD14, anti-CD18, or
anti-CD11b Abs had similar inhibitory effects when using LPS or
E. coli (Fig. 1). However, anti-CD11c had no effects on
LPS-induced cell activation either in the presence or in the absence of
serum. This was at variance with the above described inhibition by
anti-CD11c with E. coli in serum-free conditions.
Fig. 2 shows experiments using GAS (upper panels) and GBS
(lower panels) as stimuli. At variance with previous
observations with LPS or E. coli, serum, anti-CD14, or
anti-CD11c did not affect GAS- or GBS-induced TNF- release. In
contrast, anti-CD18 or anti-CD11b produced marked inhibition
both in the absence and in the presence of serum. However, these
anti-CR3 mAbs did not affect TNF- release by S.
aureus and L. monocytogenes (Fig. 3). Anti-CD11c
produced moderate, but significant (p < 0.05),
inhibition in S. aureus- or L.
monocytogenes-induced TNF- responses. Neither anti-CD14 nor
serum affected S. aureus- or L.
monocytogenes-induced stimulation (Fig. 3). Results obtained by
measuring TNF- with ELISA produced virtually identical results as to
the inhibitory effects of the various Abs (not shown). In further
studies, the experiments presented in Figs. 2 and 3 were repeated using
decreasing doses of anti-receptor Abs. The minimal concentration of
either anti-CD18 or anti-CD11b that could still produce
significant (p < 0.05) inhibitory effects was
5 µg/ml using either GBS or GAS as stimuli. With anti-CD11c Abs,
minimal inhibitory concentrations were 10 and 20 µg/ml, respectively,
using listeria and staphylococci (not shown).
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To analyze the role of CD14, CR3, and CR4 in the absence of
competing receptors or small amounts of complement products produced by
phagocytes, we used transfected cell lines, i.e., CHO cells expressing
CD14, CR3, or CR4. Control CHO/NEO cells did not produce detectable
IL-6 in the presence of bacteria or LPS (not shown). Fig. 4 shows that even in the absence of
serum, moderate production of IL-6 was observed in CD14 transfectants
stimulated with LPS (10 µg/ml) or E. coli
(p < 0.05). Similar results were observed with
lower LPS concentrations (1 and 0.1 µg/ml, not shown). Serum
increased IL-6 release induced by either E. coli or LPS
(p < 0.05; Fig. 4). In contrast, no IL-6
production was detectable in CHO/CD14 cells using any of the
Gram-positive bacteria as stimuli either in the absence or in the
presence of serum (Fig. 4).
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). In those cells, E. coli or
LPS were also capable of triggering moderate IL-6 release, but only in
the presence of serum. Conversely, S. aureus and L.
monocytogenes were not capable of inducing IL-6 release in
CR3-transfected cells. However, these bacteria induced moderate
(p < 0.05) IL-6 production in CR4
transfectants (Fig. 6). Using these
cells, either E. coli or LPS triggered moderate IL-6
release, and this effect was augmented by serum. Coexpression of CD14
with either CR3 or CR4 did not increase the ability of these cells to
respond to any of the bacterial stimuli-relative cells expressing only
one receptor (data not shown). Collectively, these transfected cell
data confirmed those previously obtained with blocking Abs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Data presented here suggest that, at least early in the signaling pathway, at the receptor level, differences may exist in responses to different bacterial species. First, CD14 appeared to play a more important role in TNF induction by E. coli or LPS, relative to any of the Gram-positive species tested. Second, different ß2 integrins may be involved in responses to streptococci on the one hand and S. aureus or L. monocytogenes on the other.
The possibility that CD14 does not play an obligatory role in monocyte
responses to whole Gram-positive bacteria is indicated by several lines
of evidence. First, anti-CD14 Abs did not prevent TNF release from
monocytes upon stimulation with Gram-positive bacteria, while almost
completely blocking responses to E. coli. Second, serum (or
combinations of soluble CD14 and LPB, our unpublished results) markedly
increased TNF induction by E. coli, but not Gram-positive
bacteria. Third, the latter organisms were unable to stimulate CD14
transfectants for increased IL-6 production. Our data are in general
agreement with those of Tuomanen et al. (35), who also
found that anti-CD14 Abs do not inhibit responses to whole
pneumococci. It was recently observed that coexpression of CD14 in CHO
cells enhanced TLR-mediated translocation of NF-
B in response to
S. aureus or S. pneumoniae (34).
Moreover, recent data from our laboratories indicate that moderate
(30%) inhibition of L. monocytogenes-induced monocyte
activation can be produced by the anti-CD14 mAb 3C10 (not
shown).
In the present study, virtually no inhibition was observed with a different anti-CD14 mAb (HB247). Therefore, it cannot be excluded that, under certain circumstances, CD14 may participate to cell activation by Gram-positive bacteria. While not ruling out this possibility, our data suggest that CD14 plays a more important role in monocyte responses to Gram-negative bacteria relative to Gram-positive ones.
This relative lack of involvement of CD14 may seem surprising, because ubiquitous and quantitatively important Gram-positive components such as peptidoglycan and acid lipoteichoic bind to CD14 and initiate cell activation phenomena through CD14-dependent pathways (9, 10, 11, 12, 13). The type-specific and group-specific polysaccharides from GBS (our unpublished results), as well as purified cell walls from GBS (30), S. aureus (36), and pneumococci (35), were also capable of inducing cytokines through CD14-dependent mechanisms.
Why should receptors involved in cytokine response to whole
Gram-positive bacteria differ from those engaged by purified
components? It is possible that some of these components may not be
expressed on the cell surface in a position or in sufficient quantities
to activate host cells. Alternatively, differences in size (i.e.,
soluble vs particulate) of the stimuli may lead to the selection of
different receptors. For example, phagocytosis, albeit not absolutely
necessary to induce TNF- responses, may provide coactivation signals
that eventually obscure those initiated by single surface components.
It is of interest that receptors mediating TNF- responses to whole
bacteria (e.g., CD14 and CR3 for, respectively, E. coli and
GBS) can also mediate nonopsonic phagocytosis of the corresponding
organism (37, 38). Interestingly, it was shown that
soluble products, specifically mannuronic acid polymers, which are
capable of activating cells only through CD14, acquire CR3 dependency
in their stimulating activity after conjugation to latex particles
(39).
In the present study, anti-CR3 Abs were highly effective in
blocking cytokine responses to GBS or GAS, but not staphylococci or
listeria. Conversely, anti-CR4 Abs inhibited TNF- release by
monocytes stimulated with staphylococci or L. monocytogenes,
but not streptococci. Experiments with transfected cells were in
general agreement with those using blocking Abs and confirmed that CR3
and CR4 may be involved in responses to streptococci on the one hand
and S. aureus and L. monocytogenes on the other.
Our GBS data are in general agreement with previous studies showing
that CR3 may mediate GBS-induced nitrous oxide production in mouse
macrophages (40). In addition, macrophage cell lines
expressing CR3, but not the WEHI 3 line that is devoid of CR3, produced
detectable TNF- after GBS stimulation (41). To our
knowledge, the involvement of CR3 in cytokine induction by GAS was not
reported. This data may be of interest in view of the ability of GAS to
induce massive cytokine release and fulminant shock in the course of
invasive infections. Although the importance of superantigenic
exotoxins in cytokine induction has been emphasized (42, 43), the potential role of whole bacteria should not be
overlooked (44).
It is perhaps too early to speculate on whether CR3 blockade can be an
effective strategy to decrease TNF production during streptococcal
sepsis. Theoretically, anti-CR3 treatments may prevent not only
streptococci-induced TNF- production, but also TNF- toxicity.
This is suggested by the ability of anti-CD18/CD11b Abs to prevent
tissue injury and cardiopulmonary changes induced by recombinant
TNF- infusion (45).
However, anti-CR3 approaches should be considered with great caution in view of the important role of these molecules in host defenses. Patients with congenital defects in the CD18/CD11b complex have impaired neutrophil functions (46, 47). In addition, anti-CD18/CD11b Abs exacerbated infection in animals challenged with E. coli (48, 49), S. aureus (50) or L. monocytogenes (51). These detrimental effects likely occurred, at least in part, as a result of decreased neutrophil adhesion to vascular endothelium and recruitment in infected sites. It will be of interest to determine whether binding of streptococci to CR3 can be selectively blocked without affecting the ability of this receptor to mediate cell to cell interactions involved in host responses. This may be feasible if bacterial- and host-derived CR3 ligands bind to different sites of this molecule. Our data do not exclude that, in addition to ß2 integrin, other receptors may be involved in such responses, especially in view of the fact that moderate responses only were observed in cells expressing single receptors. In this respect, the role of TLR should be further investigated, in view of the ability of TLR2 expression in CHO cells to confer responsiveness to staphylococci and streptococci. Studies are underway to address this point.
In conclusion, our data indicate that CR3 is involved in TNF-
induction by streptococci. In addition, CR4 may be also involved in
responses to L. monocytogenes or S. aureus.
Clearly other receptors, in addition to CR4, may play a significant
role in listeria- or S. aureus-induced stimulation. In fact,
using these bacteria, the inhibitory effects of anti-CD11c Abs were
more modest relative to those induced, for example, by anti-CR3 Abs
using GBS as a stimulus. Data presented here may be useful to devise
alternative therapeutic strategies aimed at preventing mediator
production. However, future studies are necessary to assess the
clinical relevance of these findings.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Giuseppe Teti, Istituto di Microbiologia, Torre Biologica (IIp.) Policlinico Universitario, Via Consolare Valeria 1, 98125 Messina, Italy.
3 Abbreviations used in this paper: CR3, complement receptor type III; TLR, Toll-like receptor; GBS, group B streptococcus; GAS, group A streptococcus; CHO, Chinese hamster ovary.
Received for publication June 29, 1999. Accepted for publication March 14, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mß2, CD11b/CD18) binds filamentous hemagglutinin of Bordetella pertussis. Cell 61:135.[Medline]
B activation and TNF production induced by lipopolysaccharide and group B streptococcal cell walls. J. Immunol. 160:4535. release by human monocytes on stimulation with lipopolysaccharide or staphylococcal peptidoglycan are partly similar. J. Infect. Dis. 173:212.[Medline]
acts as an autocrine second signal with gamma interferon to induce nitric oxide in group B streptococcus-treated macrophages. Infect. Immun. 63:3715.[Abstract]
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