Departments of 1 Experimental Internal Medicine, 2 Intensive Care Medicine, 3 Pathology, and 6 Infectious Diseases, Tropical Medicine, and AIDS, Academic Medical Center of Amsterdam, 1105 AZ Amsterdam, The Netherlands; 4 Amgen, Incorporated, Thousand Oaks, California 91320; and 5 University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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Pneumonia is associated with elevated
concentrations of the proinflammatory cytokine interleukin (IL)-1 in
the pulmonary compartment. To study the role of IL-1 in the
pathogenesis of Pseudomonas pneumonia, IL-1 receptor type 1 gene-deficient (IL-1R /
) mice and wild-type mice were
intranasally inoculated with Pseudomonas aeruginosa. The
absence of the IL-1 signal attenuated the outgrowth of
Pseudomonas in lungs, as reflected by an increasing number
of colony-forming units (cfu) during Pseudomonas
pneumonia in wild-type mice and a concurrently decreasing number of cfu
during pulmonary infection in IL-1R
/
mice
(P < 0.05, IL-1R
/
mice vs. wild-type
mice). Influx of neutrophils was decreased in bronchoalveolar lavage fluids in IL-1R
/
mice compared with wild-type mice.
Similarly, lung levels of cytokines (tumor necrosis factor-
, IL-6)
and chemokines (macrophage inflammatory protein-2 and KC) were lower in
IL-1R
/
mice 24 h postinoculation. Consistent with
results obtained in IL-1R
/
mice, treatment of wild-type
mice with IL-1R antagonist also diminished outgrowth of
Pseudomonas when compared with wild-type mice treated with
vehicle (P < 0.05). These results demonstrate that an
absence or reduction in endogenous IL-1 activity improves host defense
against Pseudomonas pneumonia while suppressing the inflammatory response.
tumor necrosis factor-; cytokines
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INTRODUCTION |
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INTERLEUKIN (IL)-1 is a potent proinflammatory cytokine that has been implicated in numerous physiological processes as well as inflammatory diseases (5). Evidence exists that IL-1 is an important mediator of pulmonary inflammation induced by bacteria and bacterial products. IL-1 is produced in lungs after intratracheal administration of lipopolysaccharide (LPS), and inhibition of IL-1 activity attenuates lung inflammation caused by LPS (28, 30). In addition, recombinant IL-1 causes neutrophilic infiltration in the lung comparable to LPS (29, 30). Elevated IL-1 levels have been found in pleural fluids of patients with empyema (25), and in patients with unilateral community-acquired pneumonia, significantly higher IL-1 concentrations have been measured in bronchoalveolar lavage fluids (BALF) from infected lungs, compared with BALF from noninvolved lungs or serum (4). Moreover, alveolar macrophages recovered from infected lungs spontaneously released more IL-1 into cell culture supernatants than macrophages evacuated from the noninvolved lung (4).
IL-1 signaling is required for the containment of infections with
intracellular microorganisms such as Listeria monocytogenes and Leishmania major and infections with the respiratory
pathogen Mycobacterium tuberculosis (9, 12,
20). However, little is known about the role of IL-1 in host
defense against respiratory bacterial pathogens. IL-1 can bind two
receptors. Whereas the IL-1R type 2 is a "decoy" receptor
(5), binding of IL-1 to IL-1R type 1 results in signal
transduction. As a consequence, IL-1R type 1 gene-deficient
(IL-1R /
) mice do not respond to IL-1 (15).
In the present study, we determined the role of endogenous IL-1 in lung
inflammation during pneumonia caused by Pseudomonas aeruginosa, the most frequent gram-negative pathogen involved in
nosocomial pneumonia (10, 11). Therefore, we compared
bacterial outgrowth, local production of cytokines and
chemokines, and neutrophil influx in IL-1R
/
and
wild-type mice during respiratory tract infection with P. aeruginosa.
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METHODS |
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Animals.
Female IL-1R /
mice backcrossed six times to a C57Bl/6
background (kindly provided by Immunex, Seattle, WA) and normal C57Bl/6 wild-type mice (Harlan, Horst, The Netherlands), 8-10 wk old, were
used in all experiments. IL-1R
/
mice were normal in
size and weight and displayed no abnormalities in leukocyte subsets (6). The protocol was approved by the Institutional Animal Care and Use Committee of the Academic Medical Center.
IL-1R antagonist. Recombinant human IL-1R antagonist (IL-1Ra) in hyaluronic acid vehicle was kindly provided by Amgen (Thousand Oaks, CA) and was given as a single intraperitoneal injection 12 h before induction of pneumonia at a dose of 100 mg/kg of body wt (1, 2). Control mice received the hyaluronic acid vehicle only.
Induction of pneumonia. P. aeruginosa (strain PA103) pneumonia was induced as described previously (22, 23). Briefly, bacteria were grown to midlogarithmic phase in Luria broth for 6 h at 37°C, harvested by centrifugation at 1,500 g for 15 min, washed twice in pyrogen-free 0.9% NaCl, and resuspended in 10 ml of 0.9% NaCl. The number of bacteria was determined by serial dilution in sterile isotonic saline and culture on blood agar plates for 16 h. Before we administered an inoculum of 50 µl of the bacterial solution intranasally, mice were lightly anaesthetized with inhaled isoflurane (Forene; Abott, Queensborough, Kent, UK). Control mice were inoculated with 50 µl of pyrogenic-free isotonic saline alone. We previously demonstrated that in this model of subacute Pseudomonas pneumonia, mortality is dependent on the number of bacteria administered intranasally (22, 23). While inoculation with 104 colony-forming units (cfu) does not cause mortality, survival decreases to 60% and 20% after administration of 105 and 106, respectively.
Preparation of blood samples and lung homogenates.
At 6 and 24 h after inoculation, mice were anesthetized with
Hypnorm (Janssen Pharmaceutica, Beerse, Belgium) and midazolam (Roche,
Mijdrecht, The Netherlands), and blood was collected from the vena cava
inferior in heparin-containing vacutainer tubes. Whole lungs were
harvested and homogenized at 4°C in 5 volumes of sterile 0.9% NaCl
in a tissue homogenizer that was carefully cleaned and disinfected with
70% alcohol after each homogenization. Serial 10-fold dilutions in
sterile isotonic saline were made of these homogenates (and blood), and
50-µl volumes were plated onto sheep blood agar plates and incubated
at 37°C and 5% CO2. Colony-forming units were counted
after 24 h. For cytokine measurements, lung homogenates were spun
at 1,500 g for 15 min at 4°C, and supernatants were
filtered through a 35-µm filter (Becton Dickenson, Lincoln Park, NJ)
and frozen at 20°C until cytokine measurement.
Bronchoalveolar lavage. At 24 h after inoculation, the trachea was exposed through a midline incision and cannulated with a sterile 22-gauge Abbocath-T catheter (Abbott, Sligo, Ireland). Bronchoalveolar lavage (BAL) was performed by instilling two 0.5-ml aliquots of 0.9% NaCl. BAL fluid (BALF; 0.9-1 ml/mouse) was retrieved, and total cell numbers and differential cell counts were determined from cytospins on each sample. BALF differential cell counts were done on cytospin preparations stained with modified Giemsa stain (Diff-Quick; Baxter, McGraw Park, IL).
Histological examination. For histopathological examination, lungs were fixed in 10% buffered Formalin, embedded in paraffin, and 4-µm sections were stained with hematoxylin and eosin.
Assays.
Cytokine and chemokine levels were measured by ELISA according to the
manufacturers' recommendations: IL-1 (R&D, Minneapolis, MN),
IL-1
(R&D), tumor necrosis factor (TNF)-
(Genzyme, Cambridge, MA), IL-6 (Pharmingen, San Diego, CA), macrophage inflammatory protein
(MIP)-2 (R&D), and KC (R&D).
Statistical analysis. All data are expressed as means ± SE. Comparisons between means were conducted using Wilcoxon's test. Significance was set at P < 0.05.
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RESULTS |
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Induction of pneumonia and IL-1 and IL-1
production.
Inoculation with P. aeruginosa induced signs of pneumonia in
all mice. Six and 24 h after inoculation with 105 cfu
P. aeruginosa, lungs appeared swollen and reddish with
multiple hemorrhages on the surface. Wet lung weights from wild-type
mice inoculated with P. aeruginosa increased by >61%,
compared with lungs from control mice inoculated with sterile
saline (P < 0.05; Fig.
1). IL-1R
/
mice
demonstrated a similar increase in wet lung weights after induction of
Pseudomonas pneumonia (nonsignificant vs. wild-type mice).
Inoculation with P. aeruginosa induced a diffuse pneumonia
in all mice. At 24 h after inoculation, lungs of mice displayed
peribronchial and perivascular inflammatory infiltrates with
endothelialitis. A heavy interstitial infiltrate of neutrophils was
observed together with influx of neutrophils in the alveoli (Fig.
2). At this time point, the intensity and composition of the inflammatory infiltrate were comparable in wild-type
mice and IL-1R
/
mice inoculated with P. aeruginosa.
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Bacterial clearance.
Having established that IL-1 and IL-1
concentrations are elevated
in lungs of mice suffering from Pseudomonas pneumonia, we
determined the role of endogenous IL-1 in the clearance of Pseudomonas from the pulmonary compartment. For this
purpose, wild-type and IL-1R
/
mice were inoculated with
105 cfu P. aeruginosa, and cfu were counted in
lungs harvested after 6 and 24 h (Fig.
4). After 6 h, the number of cfu
recovered from lungs was similar in IL-1 R
/
mice and wild-type
mice. In wild-type mice, the number of cfu in lungs slightly increased
between 6 and 24 h postinoculation. By contrast, IL-1R
/
mice demonstrated a >2 log decrease in P. aeruginosa
cfu during this time period. Consequently, IL-1R
/
mice
had significantly fewer cfu in their lungs at 24 h after the
induction of pneumonia than did wild-type mice (P < 0.05).
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Bacterial clearance in mice treated with IL-1Ra.
Compensatory immune mechanisms may develop in mice that genetically
lack the IL-1 signaling pathway. To determine whether the differences
between IL-1R /
and wild-type mice were caused solely by
the absence of the IL-1 receptor, we inoculated wild-type mice with
2 × 105 cfu P. aeruginosa 12 h after
intraperitoneal injection of IL-1Ra or vehicle. The results from the
first series of experiments could be recapitulated in this experiment,
i.e., IL-1Ra treatment reduced the number of cfu recovered from lungs
at 24 h postinfection compared with treatment with vehicle
(P < 0.05; Fig. 5).
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Cytokine and chemokine levels in lung homogenates.
Local production of cytokines and chemokines within the pulmonary
compartment can influence antibacterial host defense mechanisms during
pneumonia (18, 24). Therefore, we measured the
concentrations of TNF, IL-6, MIP-2, and KC in lung homogenates after
inoculation with P. aeruginosa (Fig.
6). At 6 h postinoculation, the lung levels of these mediators were similar in wild-type mice and
IL-1R /
mice. At 24 h, TNF, IL-6, KC, and MIP-2
levels were all significantly lower in lung homogenates from
IL-1R
/
mice compared with wild-type mice
(P < 0.05).
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Cell influx.
Pseudomonas pneumonia was associated with a profound influx
of neutrophils into the BALF (Table 1).
At 24 h postinoculation, IL-1R /
mice had less
neutrophils in their BALF than did wild-type mice (P < 0.05).
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DISCUSSION |
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In local infection, like pneumonia, the initiation, maintenance,
and resolution of inflammation are considered to be dependent upon the
expression of the complex network of proinflammatory and
anti-inflammatory cytokines (18, 24). In the present
study, we evaluated the role of IL-1 in the innate immune response in the pulmonary compartment during pneumonia induced by P. aeruginosa. IL-1R /
mice were found to have an
increased resistance against Pseudomonas pneumonia, as
reflected by an enhanced clearance of bacteria from the lungs, which
was associated with reduced local cytokine and chemokine concentrations
and a diminished neutrophil recruitment. These results could be
recapitulated in normal wild-type mice treated with IL-1Ra, indicating
that compensatory immune mechanisms that could have developed in mice
that genetically lack the type 1 IL-1R are unlikely to be responsible
for the present findings.
The role of cytokines in host defense against Pseudomonas
pneumonia has been investigated in several previous studies. The overall conclusion that can be drawn from these investigations is that
proinflammatory cytokines induced by P. aeruginosa in models
of subacute pneumonia likely impair bacterial clearance from the
pulmonary compartment. Indeed, treatment of mice with the
anti-inflammatory cytokine IL-10 resulted in a diminished bacterial
outgrowth in a model of subacute Pseudomonas pneumonia highly similar to our model (21). Furthermore, mice
deficient for the type 1 TNF receptor demonstrated an enhanced early
clearance of P. aeruginosa from the lungs during subacute
pneumonia (26). Similarly, we recently found that
interferon- receptor-deficient mice had an accelerated clearance of
Pseudomonas from their lungs when compared with normal
wild-type mice (23). Our present results are in line with
these published reports, i.e., the absence of the proinflammatory IL-1
signal was associated with an improved clearance of
Pseudomonas from the lung compartment. The difference between IL-1R
/
and wild-type mice became apparent after
24 h, which differs somewhat from earlier data in TNF
receptor-deficient mice that demonstrated lower Pseudomonas
cfu already at 4 h postinoculation (26). It should be
noted in this context that the role of TNF in Pseudomonas
pneumonia is not undebated, considering that other authors have
reported no effect (19) or an adverse effect
(14) of inhibition of endogenously produced TNF on the
clearance of Pseudomonas during subacute pneumonia.
It is important to emphasize that the role of cytokines in the innate immune response to respiratory tract infections differs in models in which different pathogens are used. Indeed, in experimental pneumonia caused by the gram-negative bacterium Klebsiella pneumoniae, proinflammatory cytokines like TNF and IL-1 (16, 31) are important for the clearance of bacteria from the lungs, whereas the anti-inflammatory cytokine IL-10 impairs host defense in this model (7). At present the cause of these overt differences with the role of cytokines in Pseudomonas pneumonia is unclear. A possible explanation includes differences in the extent and rapidity by which these strains induce inflammation in the lung. One could speculate that during Pseudomonas pneumonia, inflammation is excessive and thereby harms the host, whereas inflammation is more limited in Klebsiella and pneumococcal pneumonia, thereby facilitating antimicrobial effector mechanisms.
The absence of endogenous IL-1 activity was associated with reduced
neutrophil numbers in BALF at 24 h postinoculation after induction
of pneumonia. The role of IL-1 in neutrophil recruitment during lung
inflammation has been documented previously by observations that
IL-1 and IL-1
can induce neutrophil influx in lungs after intratracheal administration to rodents (13, 17, 30) and that inhibition of endogenous IL-1 activity attenuated neutrophil influx in BALF induced by LPS (17). The lower lung
concentrations of the potent chemoattractants MIP-2 and KC may also
have contributed to the diminished neutrophil recruitments in
IL-1R
/
mice, considering that they have been found to
play an important role in this inflammation response (8,
27). Alternatively, the lower bacterial load in lungs of
IL-1R
/
mice (providing less proinflammatory stimuli) could have been responsible for the attenuated neutrophil recruitment at later time points. Similarly, the higher concentrations of TNF,
IL-6, KC, and MIP-2 in lungs of wild-type mice compared with IL-1R
/
mice at 24 h after inoculation with
P. aeruginosa could be directly proportional to the number
of bacteria present at that moment.
Interestingly, IL-1R /
mice were recently reported to
have a reduced susceptibility to persistent Staphylococcal
epidermidis infection in a model of biomaterial-associated
infection (3). Hence, these data taken together with the
present results suggest that endogenous IL-1 may hamper antimicrobial
defense in at least some infections.
In conclusion we found an increased bacterial clearance in mice with a disrupted IL-1R gene during pneumonia caused by P. aeruginosa. These data exemplify the complex role of IL-1 in innate immunity during pulmonary infection and may have important implications for the development and use of cytokine/anticytokine therapies in the future.
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ACKNOWLEDGEMENTS |
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We thank Dr. B. Iglewski for providing P. aeruginosa strain 103.
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FOOTNOTES |
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T. van der Poll is a fellow of the Royal Netherlands Academy of Arts and Sciences.
Address for reprint requests and other correspondence: M. J. Schultz, Academic Medical Center, Univ. of Amsterdam, Dept. of Intensive Care Medicine, C3-326, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (E-mail: m.j.schultz{at}amc.uva.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00461.2000
Received 20 December 2000; accepted in final form 17 October 2001.
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