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Abstract |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by granuloma formation.
We recently showed that interferon-
(IFN-) is essential for inflammation and granuloma formation in
HP. Interleukin-10 (IL-10) counteracts many of the biologic effects of IFN-, suggesting that IL-10 modulates inflammation and granuloma formation in HP. We compared the expression of HP in C57BL/6 mice
that lack IL-10 (IL-10 knockout [KO]) with that in wild-type (WT) littermates. IL-10 KO and WT mice
were exposed to the thermophilic bacteria Saccharopolyspora rectivirgula or to saline alone for 3 wk. The
IL-10 KO mice had higher cell counts in their bronchoalveolar lavage fluid (2.85 ± 0.43 × 106) than did
WT mice (1.4 ± 0.3 × 106/ml; P < 0.03), with a more prominent neutrophil response. They also had
greater inflammation after antigen exposure than did the WT mice (P < 0.0001). There was increased upregulation of IFN-, IL-1, and tumor necrosis factor-
(TNF-) mRNAs in the lungs of IL-10 KO mice.
Adenovirus-mediated gene transfer of IL-10 to the liver of IL-10 KO mice reduced the inflammation from
that seen in WT mice. These studies show that IL-10 has important anti-inflammatory properties in HP,
and that lack of this cytokine leads to a more severe granulomatous inflammatory response.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Hypersensitivity pneumonitis (HP) is caused by sensitization to and repeated inhalation of various organic antigens (1). The most common of these antigens are thermophilic actinomycetes that cause farmer's lung disease (2). Repeated exposures lead to granuloma formation in the lung and, in some patients, progression to end-stage lung disease with respiratory failure and cor pulmonale (1, 2, 8). Both immune-complex-mediated immunity and cell-mediated immunity are thought to be important for the pathogenesis of HP (9). The first response to antigen is an increase in polymorphonuclear leukocytes (PMN) in the alveoli and small airways (12). This is followed by an influx of mononuclear cells and formation of granulomas (1).
Mice exposed to the actinomycete Saccharopolyspora
rectivirgula (SR; previous names Micropolyspora faeni and
Faenia rectivirgula) or other thermophilic bacteria develop
diffuse bronchoalveolitis and granulomas in the lung (15-
21). With this murine model, we have previously shown
that interferon- (IFN-) is essential for granuloma formation (21). Interleukin-10 (IL-10) is an important anti-
inflammatory cytokine that can inhibit the production of many proinflammatory cytokines, including IFN-, tumor
necrosis factor- (TNF-), and interleukin-1
(IL-1)
(22). Both human and animal studies have shown that
these proinflammatory cytokines play an important role in
the pathogenesis of HP and other granulomatous lung diseases (26).
On the basis of these observations, we hypothesized that IL-10 is important for modulation of the inflammatory response in HP, and that lack of IL-10 would lead to a more severe inflammatory response and granuloma formation. No studies have previously evaluated the role of IL-10 in HP.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Animals
C57BL/6 mice with a targeted disruption of the IL-10 gene (replacement of a 500-bp fragment containing codons 5 to 55 of the first exon by a linker providing a termination codon, by a neo expression cassette, and by introduction of a termination codon into exon 3) (32) and wild-type (WT) littermates were purchased from Jackson Laboratories (Bar Harbor, ME). They were bred and raised in the Animal Care Facility at the University of Iowa. Female mice aged 8 to 11 wk were used for these studies. Previous studies have shown that at this age the IL-10 knockout (KO) mice do not have any significant pathologic findings in their lungs (32). The mouse were housed in an antigen-free and virus-free environment, and were maintained with standard mouse chow and water ad libitum. All procedures used in the study were in compliance with Animal Welfare Act Regulations and with the Guide for the Care and Use of Laboratory Animals (33).
Antigen
Antigen was prepared from a strain of SR obtained from the American Type Culture Collection (Catalog No. 29034; ATCC, Rockville, MD). It was grown in a trypticase soy broth in a shaking incubator at 55°C for 4 d, centrifuged, and washed three times with distilled water. The washed culture was then homogenized and lyophilized. Antigen was resuspended in pyrogen-free saline. A Limulus amebocyte lysate assay (Sigma Chemical Co., St. Louis, MO) showed that this material contained less than 20 ng/ ml of endotoxin.
Induction of HP
HP was induced by instilling intranasally and under light anesthesia 150 µg of SR antigen in saline, as previously described (21). The material was applied at the tip of the nose and inhaled involuntarily. This was done for three consecutive days per week for 3 wk. We found that this was the optimal timing and dosing schedule (21). Previous studies have shown that 15 to 60% of the administered antigen reaches the lung under these conditions (34). Mice were killed with pentobarbital injection 4 d after the last antigen exposure.
Bronchoalveolar Lavage
After euthanasia, a 20-gauge catheter was inserted into the trachea. Samples of bronchoalveolar lavage fluid (BALF) were obtained by washing the lungs with three 1-ml aliquots of 0.9% saline. After centrifugation, BALF cell pellets were washed and resuspended in Hanks' balanced salt solution (HBSS), and total cell counts were made with a Coulter counter (Coulter Electronics, Hialeah, FL). Cytospin preparations were fixed and stained with Diff-Quik stain (Baxter, McGaw Park, IL). Differential counts were made on 200 cells, using standard morphologic criteria to identify the cells as neutrophils, eosinophils, lymphocytes, or macrophages.
Histologic Evaluation
Lungs were perfused with 2% paraformaldehyde through the heart and trachea, and were fixed in 2% paraformaldehyde-phosphate-buffered saline (PBS). The sections were embedded in paraffin, cut in 5-µm-thick sections and stained with hematoxylin and eosin (H&E). The sections were evaluated with light microscopy. The slides were evaluated without knowledge of the type of mouse or antigen exposure. The lung fields were evaluated for extent of inflammation and granuloma formation, and this was expressed as a percentage of the total area of the lung fields. The area covered by an eyepiece grid (0.99 × 0.99 mm, using ×100 magnification) was judged to be normal or abnormal. An average of 200 fields was evaluated for each mouse (17, 18, 21). The results of evaluation of the inflammatory changes were reproducible for two evaluations (r = 0.927).
Northern Blot Analysis
Total lung RNA was prepared using the guanidine isothiocyanate extraction and cesium chloride centrifugation method
of Chirgwin and colleagues (35), as modified by Maniatis
and coworkers (36). The RNA was fractionated on 1.5%
agarose gels containing 2.2 M formaldehyde by the method
of Lehrach and coworkers (37). The gels were stained with
ethidium bromide and destained overnight in 0.1% ammonium acetate to assess RNA integrity and equivalent loading. Escherichia coli 23S and 16S messenger RNA (mRNA)
served as standards. Subsequently, the RNA was transferred to Gene Screen Plus (NEN Research Products, Boston, MA), following the manufacturer's specifications, and
was then crosslinked to the nylon membrane by exposure
to UV light. Fixed membranes were prehybridized for 12 to 24 h at 42°C in a solution of 50% formamide, 1 M NaCl,
1× Denhardt's solution, 0.05 M Tris (hydroxymethyl) aminomethane (Tris), 1% sodium dodecyl sulfate (SDS), and
10% dextran sulfate. The membranes were hybridized in
fresh solution at 42°C with 32P-labeled complementary DNA
(cDNA) probes for murine IFN-, TNF-, or IL-1 obtained
from Clontech (Palo Alto, CA). After hybridization, the
filters were washed twice at room temperature in 1× standard saline citrate (SSC), followed by two rinses at 65°C in
1× SSC-1% SDS and a final room-temperature wash in
0.1× SSC. Hybridized membranes were then exposed to
radiographic film.
Generation of Recombinant Adenovirus Expressing Human IL-10
Human IL10 (hIL-10) cDNA was obtained by polymerase
chain reaction (PCR) with 5' and 3' flanking primers (5'-hIL-10BamHI: 5'-CGCGGATCCCATGCACAGCTCAGCACTG-3'; 3'-hIL-10BamHI: 5'-CGCGGATCCGCCACCCTGATGTCTCAGT-3'), using the clone pSRhIL-10 as
template (kindly provided by E. Field, University of Iowa).
The PCR product was cloned, using the BamHI restriction-site tails added to the oligonucleotide sequences, in a
shuttle plasmid (pAdRSV4; 31). This shuttle plasmid contains the Rous sarcoma virus promoter, the SV40-polyA
signal, and the genomic adenoviral sequences from 0 to 1 and 9 to 16 map units of human adenovirus type 5. Recombinant adenovirus expressing IL-10 was generated by homologous recombination between pAdRSVhIL-10 and human adenovirus serotype 5 derivative d1309, using standard methods (37). AdRSVLacZ has the same viral backbone
as AdRSVhIL-10, and has been described previously (37).
AdRSVLacZ expresses the gene for E. coli -galactosidase.
In Vitro Evaluation of hIL-10 Bioactivity after AdRSVhIL-10 Gene Transfer
An in vitro functional assay for hIL-10 was performed to
test the activity of AdRSVhIL-10, on the basis of the ability of IL-10 to inhibit the synthesis of IFN- by lectin-stimulated spleen cells. Six-week-old C57Bl/6 splenocytes were
isolated with a Ficoll gradient (Pharmacia LKB, Piscataway, NJ), and were incubated for 48 h at 37°C under 5%
CO2 in RPMI 1640-10 complete medium, with dilutions of
conditioned medium (CM) from HeLa cells previously infected with AdRSVhIL-10. Final concentrations of 4 µg/
ml of concanavalin A (Con A) (Sigma) to stimulate spleen
cells, and 2 ng/ml of recombinant hIL-2 (Genzyme; Cambridge, MA) to enhance the IFN- synthesis, were added
at the same time. Untreated cells and CM harvested from
cells transduced with AdRSVLacZ were used as negative
controls. Different concentrations of recombinant hIL-10
were added as positive controls. All conditions were assayed in duplicate. Mouse IFN- levels were determined
with the Intertest Mouse IFN- enzyme-linked immunosorbent assay (ELISA) kit (Genzyme). Bioactivity of hIL-10 is described as a 10 to 30% inhibition of IFN- synthesis
compared with untreated controls (39).
In Vivo Evaluation of hIL-10 Bioactivity after AdRSVhIL-10 Gene Transfer to IL-10 KO Mice
Recombinant hIL-10 has previously been shown to protect IL-10 KO mice from lipopolysaccharide (LPS)-induced shock (40). To test the bioactivity of AdRSVIL-10 in vivo, we injected IL-10 KO mice with 5 × 108 pfu of AdRSVhIL-10 or AdRSVLacZ via a tail vein. Six days later, hIL-10 levels in blood were measured with the ELISA (Genzyme) mentioned previously. All mice were challenged with a lethal dose of LPS (10 µg) injected into the tail vein. Animals were monitored for survival during the following 72 h.
In a separate experiment, groups of IL-10 KO mice were injected in the tail vein with AdRSVhIL-10 or AdRSVLacZ to test for effects in the HP model. They were given 1 × 109 pfu of virus in 100 µl of PBS with 3% sucrose. Control animals received injections of PBS. Intranasal exposures to the SR antigen or saline were started 7 d after the tail vein injections, after hIL-10 production had been confirmed by measurement of hIL-10 in the blood of the mice.
Statistics
Statistical analysis was done with an unpaired (two-tailed) t test. Values are expressed as means ± SEM. Values of P < 0.05 were considered significant. Comparisons of histologic evaluations were done with one-way analysis of variance (ANOVA), with Tukey's procedure for multiple comparisons. Probit transformation was done on percent data, with the probit value of 0.1% replacing 0%.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Bronchoalveolar Lavage
Exposure to antigen led to an increase in the total numbers of cells in BALF from both IL-10 KO and WT mice, as shown in Table 1. However, the IL-10 mice had significantly higher total cell counts in their BALF (2.85 ± 0.43 × 106/ml) than did the WT mice (1.4 ± 0.3 × 106). This was a significant difference (P < 0.03). Table 1 also shows the differential cell counts and demonstrates that both IL-10 KO and WT mice had increases in lymphocytes (60-fold and 35-fold, respectively). Also notable was the difference between the neutrophil response in the antigen-exposed IL-10 KO mice and that of the WT mice (P < 0.01). IL-10 KO mice had a 140-fold increase in neutrophils in their BALF whereas neutrophil influx in the WT mice was modest. These studies show that IL-10 modulates the cellular composition of BALF in HP.
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Histology
We have previously shown that antigen exposure results in
an inflammatory response and granuloma formation in WT
mice (21). Figure 1 shows that the severity of the inflammatory response and granuloma formation are greater in
IL-10 KO mice. Saline-exposed WT or IL-10 KO mice had
no evidence of inflammation or granulomas. The cross-sectional area of lung involved in granulomatous inflammation after antigen exposure was significantly greater in
the IL-10 KO mice (76.1%, mean 
SEM = 73.1%, mean + SEM = 79%) than in the WT mice (46.6%, mean SEM = 42.9%, mean + SEM = 50.4%), as shown in Figure 1 (P < 0.0001). This percentage underestimates the severity of inflammation in the IL-10 KO mice, because involved areas
had more dense inflammation in these mice than in the
WT mice (Figure 2). There is a potential for sampling errors with this method. For this reason, we examined a
large number of fields (n = 200 in each animal). These
studies show that IL-10 modulates the severity of inflammation and granuloma formation in HP.
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Proinflammatory Cytokine Expression
It has been suggested that IFN-, TNF-, and IL-1 are
necessary for granuloma formation in other models of
granulomatous lung disease (25). Amounts of these cytokines in lungs are too low for measurement of their protein. Therefore, we measured mRNA levels for these cytokines in lung homogenates. When exposed to the SR
antigen, the IL-10 KO mice had qualitatively more of the mRNAs for IFN-, IL-1, and TNF- in lung homogenates
(Figure 3) than did the WT mice. These observations suggest that IL-10 modulates the severity of HP by dampening the upregulation of cytokines that mediate inflammation and granuloma formation.
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Human IL-10 Adenovirus
To confirm that the more severe response in IL-10 KO
mice was due to the absence of IL-10 and not to another
developmental process, we constructed a recombinant adenovirus vector expressing IL-10 for IL-10 replacement.
The hIL-10-expressing adenovirus was tested for its bioactivity with an in vitro assay based on the ability of IL-10 to
inhibit IFN- production by lectin-stimulated spleen cells.
HeLa cells were infected with AdRSVhIL-10 or AdRSVLacZ, and the CM were collected after 24 h. CM from
AdRSVhIL-10-infected HeLa cells was able to inhibit
IFN- production by approximately 26% compared with
that in nontransfected cells (Figure 4). Neither CM from
HeLa cells infected with AdRSVLacZ nor a 1:50 dilution of CM from AdRSVhIL-10-infected cells inhibited IFN-
production. Thus, AdRSVhIL-10 is bioactive in vitro, and
inhibits IFN- expression in lectin-stimulated murine
spleen cells in a dose-dependent manner.
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In Vivo Bioactivity of AdRSVhIL-10 and Effects of Gene Transfer on HP
To test the bioactivity of AdRSVIL-10 in vivo, we administered 4 × 108 pfu of AdRSVhIL-10 or AdRSVLacZ intravenously to IL-10 KO mice. Human IL-10 levels in sera were measured at Day 6. On Day 9, 10 µg of LPS was administered intravenously, and the animals' survival was monitored for the next 72 h (Figure 5). Normal mice of the same genetic background were not affected by this amount of LPS (data not shown). All IL-10 KO mice treated with AdRSVLacZ succumbed to the endotoxin, whereas four of six mice treated with AdRSVhIL-10 survived. The levels of hIL-10 found in sera show that 200 pg/ ml of hIL-10 was able to protect IL-10 KO mice from death caused by LPS.
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In separate experiments, we replaced IL-10 through adenovirus-mediated gene transfer to the livers of IL-10 KO
mice prior to induction of HP, to confirm the role of IL-10
in HP. Mice that received AdRSVIL-10 had 48 ± 16 ng/ml
of hIL-10 in their blood at 7 d after injection of the viral
vector. In these experiments, no hIL-10 was detected in
AdRSVLacZ-injected animals (data not shown). Intranasal injections with SR or saline were initiated at this time.
Upon killing of animals, histologic analysis revealed that
IL-10 KO mice given AdRSVIL-10 had less granulomatous inflammation (46.6%, mean SEM = 41.3%, mean + SEM = 52.0%) than did mice that received the control
adenovirus vector AdRSVLacZ (66.5%, mean SEM = 62.6%, mean + SEM = 70.2%), as shown in Figure 6 (P < 0.0001). This suggests that the more severe inflammatory response to antigen seen in IL-10 KO mice was due to the
absence of IL-10.
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Discussion |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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The goal of this study was to evaluate the role of IL-10 in
the pathogenesis of HP. To address this question, we compared the development of HP in mice that express the IL-10 gene with that in mice of the same genetic background
(C57BL/6) that cannot express this gene. We found that
when IL-10 KO mice were exposed to antigen, they accumulated more inflammatory cells in their BALF and had
greater histologic evidence of inflammation and granuloma formation than did WT mice. IFN-, TNF-, and IL-1
have been shown to mediate the development of granulomas in other models of granulomatous disease (25).
The IL-10 KO mice also expressed higher levels of IFN-,
TNF-, and IL-1 mRNA in their lungs after exposure to antigen. These observations suggest that IL-10 modulates,
at least in part, the severity of HP by dampening the upregulation of IFN-, TNF-, and IL-1 genes in lung.
In a murine model of allergic bronchopulmonary aspergillosis, Grunig and associates (41) also found that IL-10
suppresses cytokine production and inflammation. Outbred
IL-10 KO mice exposed to Aspergillus fumigatus developed a neutrophilic response in their BALF, with high levels of IFN- and IL-5 in the BALF and increased inflammation as documented by histologic evaluation, compared
with WT mice. However, IL-10 KO mice of a C57BL/6 background had similar amounts of inflammation to those of
WT mice with an eosinophilic response in their BALF, and
no differences were found in IFN-. These studies, although
in a different disease model than ours, support the findings
of the current study.
Macrophages and lymphocytes are important cellular
mediators of the granulomatous inflammatory response in
lung. These cells produce several proinflammatory cytokines, including IL-1, TNF-, and IFN-. We have previously shown that IFN- is essential for granuloma formation in HP, and that mice that lack production of IFN- do
not form granulomas when exposed to antigen (21). That
study and others (27, 28, 30) suggested that IFN-, TNF-,
and IL-1 are important for the cellular immune responses leading to granuloma formation. In studies of both humans and mice, the initial response to antigen in alveoli
and small airways is an increase in PMN (12, 16). Later,
lymphocytes become more prominent. The present study
shows that a prominent neutrophil response was still evident 4 d after exposure to SA antigen in IL-10 KO mice.
This was not seen in WT mice given the same dose of SR
antigen, and demonstrates that IL-10 is important for cellular responses in HP.
IL-10 is produced by many different cell types, including B and T lymphocytes and macrophages, and affects
both those cells and others, such as neutrophils (42). In addition to inhibiting the proinflammatory cytokines IFN-,
TNF-, and IL-1, IL-10 also inhibits the production of
chemokines that are powerful chemoattractants for neutrophils (43). As a consequence, IL-10 KO mice have a more prominent neutrophil response to antigen. The sustained neutrophil response in IL-10 KO mice could further
magnify the inflammatory response, because neutrophils
are important in mononuclear cell recruitment. It is of interest that macrophages both produce and respond to IL-10 (23). It has been proposed that the production of IL-10
by macrophages provides a mechanism whereby these
cells limit their own participation and that of other cells in
antigen-driven reactions (44).
To evaluate whether the changes seen in the IL-10 KO mice were due to lack of expression of the deleted gene or were a result of a compensatory developmental process, hIL-10 was provided by adenovirus-mediated gene transfer to the liver. This route was chosen because it was previously well established as producing detectable levels of hIL-10 in serum over the time period during which intranasal injections of SR antigen take place in this murine model of HP. This resulted in decreased inflammation in these animals upon exposure to antigen, and suggests that the increased inflammatory response to antigen in IL-10 KO mice is due to lack of this important cytokine. The observations in this study show that the IL-10 dampens the inflammatory response in a murine model of HP. These results further suggest that the IL-10 response to antigen inhalation is important in the expression of disease in patients with HP. It is possible that individuals who are resistant to developing HP have prominent IL-10 responses that help to dampen the proinflammatory response that occurs with inhalation of the organic antigens that cause HP. These studies also suggest that IL-10 can be used to treat patients with HP. Further studies of gene therapy with IL-10, not only with hepatic expression but also with intratracheal expression, might be warranted in some patients with this disease.
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Footnotes |
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Address correspondence to: Gunnar Gudmundsson, University of Iowa College of Medicine GH C-321, 200 Hawkins Drive, Iowa City, IA 52242. E-mail: gunnar-gudmundsson{at}uiowa.edu
(Received in original form August 25, 1997 and in revised form March 19, 1998).
Acknowledgments: Supported in part by a VA Merit Grant, and Grants HL-37121 and AI35018 from the National Institutes of Health. Dr. Gudmundsson is funded in part by a Research Fellowship Grant from the American Lung Association of Iowa, a NATO Science Fellowship, a Research Fellowship Grant from the American Heart Association, Iowa affiliate, and the National Institute for Environmental Health Sciences Research Center Grant NIEHS/NIH P30 ESO5605. Dr. Davidson is a fellow of the Roy J. Carver Trust.
The authors thank Anita Riggan for outstanding secretarial assistance and Jannell Pemberton for technical assistance. They also acknowledge the University of Iowa Gene Transfer Vector Core, supported in part by the Carver Foundation, for providing purified viral stocks.
Abbreviations
cDNA, complementary DNA;
CM, conditioned medium;
HP, hypersensitivity pneumonitis;
IFN-, interferon-;
IL-10, interleukin-10;
LPS, lipopolysaccharide;
PCR, polymerase chain reaction;
TNA-, tumor necrosis factor-.
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References |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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