 , IL-6, and TNF- Enhance
In Vitro Growth of Bacteria
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We have previously reported that in acute respiratory distress syndrome (ARDS), nonsurvivors have
persistent elevation in pulmonary and circulating proinflammatory cytokine levels over time and a
high rate of nosocomial infections antemortem. In these patients, none of the proven or suspected
nosocomial infections caused a transient or sustained increase in plasma proinflammatory cytokine
levels above preinfection values. We hypothesized that cytokines secreted by the host during ARDS
may favor the growth of bacteria. We conducted an in vitro study of the growth of three bacteria clinically relevant in nosocomial infections, evaluating their in vitro response to various concentrations of
tumor necrosis factor (TNF)-
, interleukin (IL)-1
, and IL-6. We found that all three bacterial species
showed concentration-dependent growth enhancement when incubated with one or more tested
cytokines and that blockade by specific neutralizing cytokine MoAb significantly inhibited cytokine-induced growth. When compared with control, the 6-h growth response (cfu/ml) was maximal with
IL-1 at 1,000 pg for Staphylococcus aureus (36 ± 16 versus 377 ± 16; p = 0.0001) and Acinetobacter spp.
(317 ± 1,147 versus 1,124 ± 147; p = 0.002) and with IL-6 at 1,000 pg for Pseudomonas aeruginosa
(99 ± 50 versus 509 ± 50; p = 0.009). The effects of cytokines were seen only with fresh isolates and
were lost with passage in vitro on bacteriologic medium without added cytokines. In this study we provide additional evidence for a newly described pathogenetic mechanism for bacterial proliferation in the presence of exaggerated and protracted inflammation.
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Cells, whether they exist as single entities or are organized into tissues, respond to signals from their environments. The ability to generate and respond to signaling molecules establishes a mechanism for regulated cell-to-cell communication. During tissue homeostasis and in response to an insult, cells coordinate their growth and proliferation with autocrine and paracrine signaling by means of low molecular weight polypeptides called cytokines.
Cytokines of the interleukin (IL)-1 and tumor necrosis factor (TNF) families have considerable overlap in their effector function and are uniquely important in initiating all key aspects of the host defense response (HDR) to an infectious or noninfectious insult (1). Once released at tissue level, these cytokines act on epithelial cells, stromal cells (fibroblasts and endothelial cells), extracellular matrix, and recruited circulating cells (neutrophils, platelets, lymphocytes) to cause secondary waves of cytokine release with amplification of the HDR (2). TNF and IL-1 have concentration-dependent biologic effects. Whereas optimal levels of these cytokines are important for a successful defense, at progressively higher concentrations they mediate proportionately stronger local and finally systemic responses (3), with predominantly destructive rather than protective effects on the host.
We have previously investigated the longitudinal relationship between pulmonary and circulatory cytokine levels, infections, and outcome in acute respiratory distress syndrome (ARDS), a frequent form of hypoxemic respiratory failure associated with mortality in excess of 50% (4). Most ARDS nonsurvivors die after a prolonged period of ventilatory support, invariably developing nosocomial infections antemortem. In these patients, ventilator-associated pneumonia (VAP) is the most frequently identified infection, and its occurrence is associated with a higher severity of illness (5). VAP is identified by postmortem histology in 48 to 73% of ARDS cases (1). Although the close association between nosocomial infections and mortality in patients with ARDS is well established, we have recently reported findings suggesting that such nosocomial infections may be intermediate steps in the causal pathway to mortality and may not be an actual cause or even a marker of an actual cause of the patient's demise.
Our previous studies showed that at the onset of ARDS
and over time, nonsurvivors had significantly (p < 0.0001)
higher plasma and bronchoalveolar lavage (BAL) TNF-, IL-1, and IL-6 levels than survivors did (6, 7). During the first
week of ARDS, cytokine levels declined in all survivors, whereas
they remained persistently elevated in all nonsurvivors. Nosocomial infections were more likely to develop in patients
with persistent cytokine elevation over time (67 versus 29%),
and none of the proven (n = 36) or suspected (n = 55) infections caused a transient or sustained increase in plasma TNF-,
IL-1, and IL-6 levels above preinfection values (8). Furthermore, in patients with unilateral pneumonia, BAL TNF-, IL-1, and IL-6 levels were similar in the BAL obtained from the
lung with significant bacterial growth compared with the BAL
from the contralateral lung without growth (8). Our findings
suggest that final outcome in patients with ARDS is related to
the magnitude and duration of the HDR and is independent
of the development of intercurrent nosocomial infections.
Among the myriad ways that microorganisms have developed to evade host defense mechanisms (9), a recent report
indicates that pathogenic Escherichia coli finds a growth advantage in the presence of IL-1 (10). Although the increase
in nosocomial infections might be explained by impaired host
defense response, an alternative might be that the host response enhances the milieu for bacterial growth. We hypothesized that cytokines secreted by the host during ARDS may
indeed favor the growth of bacteria and explain the association between an exaggerated and protracted release of cytokines and the frequent development of nosocomial infections.
To test this hypothesis, we conducted an in vitro study of the
growth of three bacteria clinically relevant in nosocomial infections and evaluated their response to various concentrations of the proinflammatory cytokines TNF-, IL-1, and IL-6.
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Bacteria
Fresh clinical bacterial isolates of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp. recovered from the bronchoalveolar lavage fluid or peripheral blood of patients admitted to the UT-Bowld Hospital were used without any additional passage in vitro to keep the biologic nature of the bacterial isolates intact as much as possible. A single colony of each organism was grown in nutrient broth and incubated at 37° C for 6 h. The cultures were then centrifuged at 2,000 × g, and the resulting bacterial pellets were resuspended in phosphate-buffered saline at a concentration of 1 × 106 bacteria/ml.
Cytokines
Functionally active and 99% pure proinflammatory cytokines IL-1,
IL-6, and TNF- expressed and purified from E. coli were obtained in
lyophilized form from R&D Systems (Minneapolis, MN). The cytokines were reconstituted in RPMI medium, aliquoted, and immediately stored at 
80° C.
Monitoring of Bacterial Growth in the Presence of Cytokines
To evaluate the growth of bacteria, two culture media were selected:
RPMI, a simple, minimal-nutrient tissue culture medium (Life Technologies, Inc., Bethesda, MD) and a synthetic medium designed for
the growth of generally nutritionally exacting bacteria (11). RPMI
medium lacks the complex organic materials that are present in a conventional bacteriologic growth medium, and has no interference with
the biologic activities of the tested cytokines. A 10-µl bacterial inoculum (1 × 105 colony-forming units [cfu]) was added to 1.0 ml of RPMI.
Cytokines IL-1, IL-6, and TNF- were added to the medium in various concentrations (10 pg, 50 pg, 100 pg, 500 pg, 1 ng, and 10 ng). Because these cytokines were lyophilized in the presence of bovine serum albumin (BSA), a 0.1% solution of BSA (Fisher Scientific, Atlanta,
GA) was used as control. The cultures were incubated at 37° C and sampled at 2, 4 to 6, and 8 h and overnight. The samples were diluted
10-fold in respective serum-free media, and 10 µl were plated onto LB
agar (Difco, Detroit, MI), and the plates were incubated at 37° C overnight (16 to 18 h). The resulting bacterial colonies were counted manually and expressed as colony-forming units (cfu)/milliliter.
The RPMI experiments were repeated using a synthetic bacteriologic medium (CDM) with the exception of deleting the overnight sample point. A 10-µl bacterial inoculum (1 × 105 cfu) of Staphylococcus aureus, Pseudomonas aeruginosa, or Acinetobacter spp. was inoculated to 1.0 ml of CDM (chemically defined medium) supplemented
with 0, 1.0, and 10.0 ng of cytokines TNF-, IL-1, or IL-6. The cultures were then incubated at 37° C for 6 h. Aliquots of these cultures
were then taken out and diluted 10-fold in antibiotic and serum-free
medium; 10 µl of these diluted cultures were then plated onto LB agar
plates. These plates were incubated for 16 to 18 h at 37° C. The resulting colonies were counted manually and expressed as cfu/ml. All of
the above experiments were run in duplicates.
Serial In Vitro Passage of Bacterial Isolates
Each bacteria was also serially passaged in vitro six consecutive times to evaluate its ability to use cytokines as growth factors after adapting to in vitro growth. The culture obtained after the sixth serial subculture was used as passed culture.
Neutralization of Biologic Activities of Cytokines
The specific nature of the action of individual cytokines was studied
by neutralizing the activities of each cytokine with respective monoclonal antibodies (MoAb). Following the manufacturer's instruction
(R&D Systems), 300 ng of anti-IL-1 MoAb was mixed with 5 ng of
recombinant human IL-1 to neutralize its biologic activity; 600 ng of
anti-IL-6 MoAb was mixed with 5 ng of recombinant human IL-6, and
4 µg of anti-TNF- MoAb was mixed with 5 ng of recombinant TNF-.
The mixtures of pure recombinant human cytokines and specific MoAbs were incubated at 4° C for 1 h and then placed on RPMI medium.
Subsequently, 1 × 105 cfu of bacteria were added to each culture and
incubated at 37 ° C for 4 to 6 h. Serial 10-fold dilutions of these cultures were made, inoculated onto LB agar plates, and incubated for 16 to 18 h before estimating bacterial concentration. The specificity of
action of cytokines was further tested by incubating pure recombinant cytokines with equivalent amounts of normal mouse immunoglobulin G (IgG) and then assessing the effects of this mixture on extracellular bacterial growth.
Statistical Analysis
For all analyses, bacterial growth, measured in cfu/ml × 106 or cfu/
ml × 107, was transformed by taking the natural logarithm of cfu/ml × 106/106 or the natural log of cfu/ml × 107/107. First, for each type of
bacteria separately, one-way analysis of variance (ANOVA) was
used to compare bacterial growth after incubating for 6 h in medium
containing various concentrations of IL-1 or IL-6. Second, growth
curves for the three types of bacteria were analyzed. After taking the
natural logarithm of time, linear regression methods were used to determine that the growth curves obtained from incubation with either
500 or 1,000 pg (1 ng) of IL-1 or IL-6 were not statistically different.
Subsequently, linear regression methods were used to estimate the
95% confidence interval for the mean number of bacteria predicted
after incubation for 8 h with either IL-1 or IL-6. Linear regression
was used to estimate the mean number of bacteria predicted after incubation for 8 h in a medium devoid of either IL-1 or IL-6. A three-way ANOVA was used to determine the effects of type of bacteria
and type of isolate (fresh or passed) on bacterial growth after incubating for 6 h in a medium that either contained or did not contain a specified concentration of IL-1 or IL-6.
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All three bacterial species tested, namely, Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp., showed concentration-dependent enhancement in growth when incubated with one or more of the tested cytokines. Among the three isolates, different results were observed with respect to specific cytokines and culture media. The effects of cytokines were seen only with fresh isolates and were lost with passage in vitro on synthetic medium.
Growth Response in RPMI Medium:
Staphylococcus aureus and IL-1
In RPMI medium, S. aureus had enhanced growth in the presence of IL-1, whereas no changes were observed with TNF- or
IL-6. The 4-h growth response in RPMI medium of two fresh isolates of S. aureus in the absence and presence of IL-1 is shown
in Figure 1. As shown in Figure 2, the 6-h growth response in
RPMI medium to increasing concentrations of IL-1 was concentration-dependent. Significant growth (× 106 cfu/ml), compared with control (36 ± 16), was observed with IL-1 at 50 pg
(55 ± 16; p = 0.035), 500 pg (280 ± 16; p = 0.0001), and a maximal response was observed at 1,000 pg (377 ± 16; p = 0.0001).
Significant growth was also observed with IL-1 at 500 pg (p = 0.0001) and 1,000 pg (p = 0.0001) in comparison with IL-1 at 50 pg. A shift to the left in the growth curve of S. aureus in response
to 500 or 1,000 pg concentration of IL-1 is demonstrated in Figure 3. Regression analysis indicated that these curves were not
significantly different, and the two were combined. After 8 h, the
95% confidence interval for the mean cfu/ml estimated from the
combined curve of 500 and 1,000 pg concentrations of IL-1 did
not contain the predicted value for the control.
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Growth Response in RPMI Medium: Pseudomonas aeruginosa and IL-6
In RPMI medium, Pseudomonas aeruginosa had enhanced
growth in the presence of IL-6, whereas no changes were observed with IL-1 or TNF-. As shown in Figure 2, the 6-h
growth response in RPMI medium to increasing concentrations of IL-6 was concentration-dependent. Significant growth
(× 106 cfu/ml), compared with control (99 ± 50), was observed with IL-6 at 500 pg (367 ± 50; p = 0.0213), and a maximal response was observed at 1,000 pg (509 ± 50; p = 0.009).
Significant growth was also observed with IL-6 at 500 pg (p = 0.0284) and 1,000 pg (p = 0.012) in comparison with IL-6 at
50 pg. A shift to the left in the growth curve of Pseudomonas
aeruginosa in response to 500 or 1,000 pg concentration of IL-6
is demonstrated in Figure 3. Regression analysis indicated these
curves were not significantly different, and the two were combined. After 8 h, the 95% confidence interval for the mean
cfu/ml estimated from the combined curve of 500 and 1,000 pg
concentrations of IL-1 did not contain the predicted value
for the control.
Growth Response in RPMI Medium:
Acinetobacter sp. and IL-1
In RPMI medium, Acinetobacter sp. had enhanced growth in
the presence of IL-1, whereas no changes were observed
with IL-6 or TNF-. As shown in Figure 2, the 6-h growth response in RPMI medium to increasing concentrations of IL-1 was concentration-dependent. Significant growth (× 106
cfu/ml), compared with control (317 ± 147), was observed
with IL-1 at 500 pg (1,039 ± 147; p = 0.002), and a maximal
response was observed at 1,000 pg (1,124 ± 147; p = 0.002).
Significant growth was also observed with IL-1 at 500 pg (p = 0.0112) and 1,000 pg (p = 0.008) in comparison with IL-1 at
50 pg. A shift to the left in the growth curve of Acinetobacter
sp. in response to 500 or 1,000 pg concentration of IL-1 is demonstrated in Figure 3.
Growth Response in RPMI Medium after Six In Vitro Passages
The difference in the 6-h RPMI medium growth response to a
1,000 pg concentration of the respective cytokine (IL-1 or
IL-6) between fresh isolates and isolates passed six times is
shown in Figure 4. After six in vitro passages, bacteria lost
their ability to respond to the tested cytokine and had no significant additional growth at 6 h. At 6 h, each fresh isolate had
a significant growth in comparison with baseline (p < 0.0001)
and with the growth of the passed isolate evaluated at 6 h (p = 0.0002).
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Growth Response in Synthetic Bacteriologic Medium
The growth of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp. in the presence of IL-1, IL-6,
and TNF- at concentrations of 0 and 1,000 pg and 10 ng was
also tested in a chemically defined synthetic bacteriologic medium (CDM). The growth of S. aureus was enhanced in the
presence of all these cytokines, in contrast to the response observed with IL-1 alone in RPMI medium (Table 1). Compared with control, significant growth (× 106 cfu/ml) was observed at 1,000 pg and at 10 ng with TNF- (control, 44 ± 19;
1,000 pg, 172 ± 19; p < 0.001 and 10 ng, 234 ± 19; p < 0.0001);
IL-1 (control, 62 ± 19; 1,000 pg, 206 ± 19; p = 0.0005 and 10 ng, 265 ± 19; p < 0.0001); and IL-6 (control, 54 ± 19; 1,000 pg,
151 ± 19; p = 0.006 and 10 ng, 224 ± 19; p = 0.0002). For
Pseudomonas aeruginosa, and Acinetobacter spp. the responses to cytokines in a synthetic bacteriologic medium were similar to those observed with RPMI medium. Pseudomonas aeruginosa had enhanced growth (× 106 cfu/ml) in the presence of
IL-6 (control, 106 ± 20; 1,000 pg, 331 ± 20; p = 0.005 and 10 ng, 402 ± 20; p = 0.002), whereas no changes were observed
with TNF- or IL-1. Acinetobacter spp. had enhanced growth
(× 106 cfu/ml) in the presence of IL-1 (control, 71.5 ± 12; 1,000 pg, 222 ± 12; p = 0.004 and 10 ng, 281 ± 12; p = 0.002),
whereas no changes were observed with TNF- or IL-6.
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Neutralization of the Biologic Activities of Cytokines
The specificity of the individual cytokine action was examined by the addition of specified antibodies to individual cytokines in the growth medium. In the presence of such neutralizing antibodies, the bacterial growth enhancement (at 6 h) of the respective cytokine was significantly inhibited (p < 0.0001) (Table 2), whereas the normal mouse immunoglobulin failed to do so. These results support the previous observation that three tested cytokines have specific effects on extracellular bacterial growth of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp.
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In the present study, we found that (1) fresh isolates of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp. are able to use in a concentration-dependent manner at least one of the three tested proinflammatory cytokines for their growth, and (2) growth enhancement in the presence of cytokines was lost after six in vitro passages. The finding that human pathogens can enhance their growth by using proinflammatory cytokines provides new insights into the cause and effect relationship in host/pathogen interactions after activation of the host defense response. After comparing our results with those of prior studies on bacterial growth in the presence of cytokines, we will discuss the relevance of our findings within the present pathogenetic understanding of unresolving ARDS.
We have extended to Staphylococcus aureus, Pseudomonas
aeruginosa, and Acinetobacter spp. the reports from Porat and
colleagues (10) on IL-1 and virulent E. coli, Denis and Gregg
(12) on Mycobacterium avium and IL-6, and Hogan and colleagues (13) on coliform bacteria and interferon-gamma. Similar to Porat and colleagues (10), we found that (1) cytokines
do not alter the numbers of bacteria at the stationary phase,
but instead affect the rate at which the stationary phase is
reached; (2) growth enhancement is concentration-dependent;
(3) blockade by specific cytokine MoAb significantly inhibits
cytokine-induced growth.
In the interaction between a microorganism and its host, the host's defense does not go unchallenged (9). Several reports have shown that DNA viruses have the ability to interfere with extracellular cytokines or inhibit cytokine synthesis. Very little is known regarding the ability of bacteria to evade or use cytokines secreted by the host cells (9). Our results indicate that in the host milieu, Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp. may acquire a phenotypic ability to use cytokines as growth factors, as indicated by the ability of the fresh isolates to use cytokines in their own growth advantage, and that the subsequent removal of these pathogens from such milieu resulted in the loss of the acquired phenotype, as evidenced by the inability of serially passed isolates to use cytokines to enhance their growth potential. This phenomenon of loss of responsiveness to cytokines is also recorded by Porat and colleagues (14), even though no explanation was offered. It is unclear how bacteria may use cytokines for their growth since bacteria are prokaryotes without a defined nucleus and cytokines are intended to work on well- defined eukaryotic cells with consequent signal transduction events. However, in a host milieu bacteria may adapt to eukaryotic cellular processes (15).
The surface of gram-negative bacteria has receptors for
proinflammatory cytokines TNF- and IL-1 (10, 16, 17), and the virulence property of the bacterium is altered as a consequence of cytokine binding (17). Although the subsequent sequence of intracellular events has not been delineated, it is
possible that bacteria might use cytokines through receptor-mediated, signal-transduction-induced activities that would
require the presence of biochemical processes akin to those
seen in eukaryotic cells; cytokines may act on bacteria through
a signaling process similar to that of eukaryotes but involving
different biochemical pathways; or bacteria may break down
cytokines into biologically active fragments that are transported across the bacterial cell membranes and act on specific
gene transcription and translation.
It has been shown that proinflammatory cytokines are pivotal in host defense mechanisms and are of central importance
in the response to bacterial infections. When bacteria reach
the alveoli, cellular mechanisms are called into action in a sequence of steps designed to deactivate or exterminate the invading pathogens, limit their replication, and remove them
from the lung (18). TNF- and IL-1 produced by the alveolar
macrophage system and other cells (19) interact with cellular
constituents of the vascular space and vessel wall, thereby setting in motion a series of events that leads to diapedesis and
activation of polymorphonuclear neutrophils (PMN). After phagocytic and microbicidal activities, PMN die, externalizing their
intracellular content in the process and perhaps causing tissue
injury (18).
Experimental and human studies have shown that a lung
affected by ARDS is impaired in its ability to clear a bacterial
challenge. Several intrinsic defects have been previously implicated, primarily those related to changes in the alveolar environment and the function of phagocytic cells (18). When
VAP develops, clinical and postmortem studies have described a strong association between the number of bacteria
and severity of inflammation (20, 21). Polymorphonuclear cells recruited into the air spaces of patients with ARDS have shown evidence of impaired microbicidal activity (22, 23); this
mechanism partly explains the lung's inability to clear bacteria despite intense local inflammation. Furthermore, PMN clearing of bacteria is dose-dependent, and the efficiency of PMN
bactericidal activity decreases with increasing bacterial load
(24). The findings of our study indicate that elevated cytokine
levels in the air spaces of patients with ARDS (7) may enhance bacterial growth and further compromise bacterial
clearance. In an earlier longitudinal study of patients with
ARDS (7), we reported that nonsurvivors had in the early
phase of the disease significantly higher (mean ± SE) bronchoalveolar lavage concentrations (pg/ml) of TNF- (5,022 ± 287 versus 1,773 ± 74; p < 0.0001), IL-1 (17,854 ± 1,405 versus 5,225 ± 372; p = 0.0002), and IL-6 (11,099 ± 547 versus
4,174 ± 192; p < 0.0001) than survivors did. Over time, nonsurvivors in contrast to survivors had persistent elevation in
bronchoalveolar lavage cytokine levels (Days 3 to 10: TNF- of 5,055 ± 506, IL-1 of 16,570 ± 2,904, and IL-6 of 11,074 ± 964; Days greater than 10: TNF- of 3,679 ± 662, IL-1 of
11,076 ± 3,359, and IL-6 of 8,649 ± 1,083); and a higher rate
of ventilator-associated pneumonia and other nosocomial infections (7, 8). In agreement with our results, the findings of
a recent experimental study of gram-negative pneumonia indicated that persistent elevation in BAL proinflammatory
cytokines is associated with failure to clear intrapulmonary
bacteria despite a large influx of PMN in the air spaces (25).
IL-6 was previously shown to impair human monocyte anti-mycobacterial properties against M. avium in a dose-dependent manner (12). To our knowledge, the relationship between
cytokine levels and function of phagocytic cells in ARDS has
not been investigated.
In this study, we provide additional evidence for a newly described pathogenetic mechanism for bacterial proliferation. The bidirectional effects of proinflammatory cytokines on bacterial growth help explain the frequent occurrence of nosocomial infections in patients with unresolving ARDS and provide additional justification for evaluating therapies directed at reducing exaggerated cytokine release in patients with dysregulated host defense response.
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Footnotes |
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Correspondence and requests for reprints should be addressed to G. Umberto Meduri, M.D., University of Tennessee, Memphis, Division of Pulmonary and Critical Care Medicine, 956 Court Avenue, Room H316, Memphis, TN 38163. E-mail: umeduri{at}utmem1.utmem.edu
(Received in original form July 16, 1998 and in revised form February 10, 1999).
Acknowledgments: The writers wish to acknowledge James B. Dale, M.D., for helpful suggestions in designing the study, Vickie S. Baselski, Ph.D., for providing the bacterial isolates, Lee Thompson for preparation of the figures, and David Armbruster, Ph.D., for editorial review.
Supported by the Assisi Foundation of Memphis and the Baptist Memorial Health Care Foundation.
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References |
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METHODS
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REFERENCES
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