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Departments of
*
Pediatrics and
Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109; and Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is the latter response for which researchers have begun to identify pharmaceutical targets that alter detrimental cytokine responses in the lung. This may help alleviate the long-term lung damage that initiates and/or maintains chronic lung problems. Recent evidence has identified several cytokines that may participate in setting up the appropriate inflammatory milieu that allows the progression of lung damage after RSV infection, leading to long-term pulmonary problems. In particular, IL-13, produced during allergic asthma, has been associated with increased mucus production, goblet cell hypertrophy, and airway hyperreactivity in animal models (17, 18). This cytokine may also be an essential molecule that contributes to the prolonged pulmonary responses leading to lung damage and airway hyperreactivity during RSV infection, thus setting the stage for long-term lung hyperresponsiveness. In these studies, the experiments were designed to examine the role of IL-13 as a pivotal cytokine for altering the anti-viral immune response, as well as in promoting a pulmonary environment that proceeds with lung dysfunction. A number of important features of the RSV infection model were examined after neutralization of IL-13, including airway hyperreactivity and mucus production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Specific pathogen-free DBA2/J mice (H-2d) were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed in University of Michigan animal facilities under pathogen-free conditions. STAT6-/- BALB/c mice (H-2d) were grown and maintained by Dr. Mark Kaplan at Indiana University (Indianapolis, IN).
Virus and infection
DBA/J mice were infected intratracheally with 30 µl (3 x 105 PFU) of human (h) RSV A2 strain wild type that was propagated in Vero cells. The virus was mycoplasma free. The level of cytokine and chemokines in the stock solution, including IL-13, was below detectable levels on our ELISAs. The mice were anesthetized with sodium pentobarbital (50 mg/kg) and ketamine (40 mg/kg) given i.p. Tracheotomy was then performed, and RSV was injected directly into the trachea via a Hamilton syringe. Control mice had culture supernatant with no RSV injected intratracheally, and no airway hyperreactivity was observed. The incision was closed with surgical staples, and mice were allowed to recover. No mice died from this level of viral infection or from anesthesia.
Determination of RSV Ags in lungs of infected mice
Total RSV Ag levels in lung homogenates were measured by a specific ELISA as previously described (19, 20). Briefly, the lung samples (50 µl) were incubated in goat anti-RSV Ab (AB1128; Chemicon, Temecula, CA)-coated 96-well plates for 60 min. After a three-step wash, the plates were incubated with a secondary Ab, a mouse anti-RSV polyclonal Ab (NCL-RSV3; Vector Laboratories, Burlingame, CA). After a final incubation with a peroxidase-labeled goat anti-mouse IgG Ab (Boehringer Mannheim, Indianapolis, IN), positive wells were assessed by tetramethylbenzidine development as the substrate. OD readings were determined at 450 nm. A standard line was constructed with samples of known viral titers, and the OD readings were used for comparison on the standard line, giving results that represent viral Ag load. It appears that the viral Ag peaks after known infectious particles in the lung and correlates to the peak in the immune response and damage. The accuracy of the ELISA in lung homogenates was verified by spiking lung samples with known quantities of virus and demonstrating recovery of the spiked sample.
Measurement of airway hyperreactivity
Airway hyperreactivity was measured using a Buxco (Troy, NY) mouse plethysmograph specifically designed for low tidal volumes as previously described (21, 22). Briefly, the mouse to be tested was anesthetized as previously described and intubated via cannulation of the trachea with an 18-gauge metal tube. The mouse was placed on a Harvard pump ventilator (tidal volume, 0.4 ml; frequency, 120 breaths/min; positive end-expiratory pressure, 2.5–3.0 cm H2O) and was ventilated for 5 min before the methacholine challenge. The plethysmograph was sealed, and readings were monitored by computer. Because the box is a closed system, a change in lung volume was represented by a change in box pressure (Pbox), which was measured by a differential transducer. The system was calibrated with a syringe that delivered a known volume of 2 ml. A second transducer was used to measure the pressure swings at the opening of the trachea tube (Paw), referenced to the body box (i.e., pleural pressure), and to provide a measure of transpulmonary pressure (Ptp = Paw - Pbox). The tracheal transducer was calibrated at a constant pressure of 20 cm H2O. Resistance was calculated using the Buxco Electronics (Sharon, CT) software by dividing the change in pressure (Ptp) by the change in flow (F) (dPtp/dF; units = cm H2O/ml/s) at two time points from the volume curve, based upon a percentage of the inspiratory volume. Once baseline levels were stabilized and initial readings were taken, a methacholine challenge was given i.v. via cannulation of one of the tail veins with a 27-gauge needle. A dose-response curve (0.001–0.5 mg) was performed, and an optimal dose of 0.4 mg/kg of methacholine was obtained. This dose was used throughout the rest of the experiments in this study. After the methacholine challenge, the response was monitored, and the peak airway resistance was recorded as a measure of airway hyperreactivity.
ELISAs
Assessment of cytokines was quantitated from homogenized (PBS) lung aqueous extracts using a double-ligand ELISA system. The murine ELISAs were developed in our laboratories using a previously described method (23). ELISAs were conducted as follows. Flat-bottom 96-well microtiter plates (Immuno-Plate I 96-F; Nunc, Naperville, IL) were coated with capture Ab diluted to 3.2 µg/ml in coating buffer (borate-buffered saline, pH 8.6) and incubated overnight at 4°C. Nonspecific binding sites were blocked with 2% BSA in PBS and incubated for 1 h at 37°C. Plates were washed, and specimens were added in triplicate, followed by incubation at 37°C and washing. Biotinylated detection Ab was added, and the plates were incubated at 37°C for 1 h. Plates were washed, and conjugated streptavidin-peroxidase was added, followed by washing and the addition of chromogen substrate (o-phenylenediamine). Finally, plates were incubated at room temperature, and the reaction was terminated with 3 M H2SO4 and read at 490 nm in an ELISA reader. The individual polypeptides were standardized to total protein (nanograms per microgram total protein). Our ELISAs routinely detect protein at concentrations above 50 pg/ml. These ELISAs are specific and do not cross-react to any other chemokine or cytokine.
Production of anti-IL-13 Abs
Rabbit anti-murine IL-13 Abs were prepared by multiple-site
immunization of New Zealand White rabbits with murine (m) rIL-13 (R&D
Systems, Rochester, MN) in CFA. Polyclonal Abs were titered by direct
ELISA and were specifically verified by the failure to cross-react to
mIL-3, mIL-1
, mTNF, mIL-4, hIL-13, mIL-10, mIL-12, murine macrophage
inflammatory protein (MIP)-1, IL-6, murine monocyte chemoattractant
protein-1, mMIP-1
, human monocyte chemoattractant protein-1, hIL-8,
hRANTES, hMIP-1, hTNF, and hMIP-1. The IgG portion of the serum
was purified over a protein A column and used in a sandwich ELISA.
Whole serum (0.5 ml) was used in vivo to block IL-13 during the RSV
infection.
In vivo neutralization of IL-13
Neutralization of IL-13 was conducted using a polyclonal rabbit
anti-mIL-13 Ab developed in our laboratory as described above. The
anti-IL-13 or control Ab was administered i.p. 1 h before
infection and every 2 days postinfection until day 12. The in vivo
half-life of the Ab was 
30 h.
Plaque-forming assay
Plaque assays were performed in a manner similar to that previously described (24). Lungs were removed and snap frozen. Tissues were homogenized on ice, and the debris was removed by centrifugation. Supernatants were added onto subconfluent Hep G2 cell monolayers in 12-well plates (Costar, Corning, Corning, NY). After 1 h of gentle agitation, plates were covered with 0.75% methylcellulose in DMEM/10% FBS and incubated for 4 days at 37°C. Monolayers were then fixed with 10% buffered formalin and stained with hematoxylin-eosin. Plaques were counted with the aid of a dissecting microscope.
Statistics
Statistical significance was determined by ANOVA, and significance was determined with p < 0.05.
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Results |
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The damage induced during pulmonary RSV infections is centered on
significant epithelial cell sloughing and mucus production that is
thought to lead to chronic airway hyperresponsiveness. Initiation of a
pulmonary infection with RSV (3 x 105 PFU)
in DBA2/J mice induced significant airway damage. This was illustrated
in several ways during the infection. Examination of lung histology
demonstrated peribronchial inflammation and edema (Fig. 1
A) and the appearance of
significant numbers of periodic acid-Schiff (PAS)-positive
mucus-producing cells (Fig. 1B), not found in uninfected
mice. The cellular infiltrate appeared to contain primarily mononuclear
cell populations with very few eosinophils present at any time
throughout the responses. The sloughing of epithelial cells and the
presence of significant mucus and cellular debris in the airway on day
12 of infection exemplified the pathological changes observed in the
bronchial alveolar washes (Fig. 1C).
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measurement of airway resistance demonstrated that the RSV-infected
DBA2/J mice had significant changes that began by day 8, continued to
increase at day 10, peaked by days 12–14, and was back near baseline
by day 20 postinfection. BALB/c/J (H-2d) mice
demonstrated airway hyperreactivity changes similar to those of the
DBA/J (H-2d) mice. The instillation of
heat-killed virus induced none of the changes observed above (data not
shown). Other strains of mice including C57BL6/J
(H-2b) and CBA/J (H-2k)
demonstrated relatively mild RSV-induced responses (data not shown).
Altogether, these data indicate significant airway damage and altered
airway physiology after RSV infection in mice with an
H-2d haplotype. These data correlate well with
previous data suggesting that RSV-induced responses are MHC restricted
(16). Thus, we continued to examine these latter strains
of mice to determine the mechanism of how they respond to RSV.
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Previous investigations have determined that the severity of
RSV-induced damage may center on the cytokine environment established
during RSV infection. To address this issue, the lungs from
RSV-infected mice were homogenized and examined for levels of specific
cytokines. A number of Th1- and Th2-associated cytokines were analyzed
including IL-4, IL-13, and IFN-
. There were significant increases
observed in IFN- at earlier time points after virus challenge (Fig. 3). When Th2-type cytokines were
examined, IL-4 levels showed little change; however, there was a
significant increase in IL-13 levels observed by day 8 post-RSV
infection (Fig. 3). This increase in pulmonary IL-13 levels paralleled
changes observed in airway hyperreactivity. From these data, it
appeared that the changes in IL-13 represented a significant alteration
in the immune response that led to the pathological changes observed
during RSV infection. These changes include mucus production and airway
hyperreactivity.
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Recent data have established an essential role for IL-13 in airway
hyperreactivity responses and mucus production (17, 18).
Because many of the pathophysiological changes in RSV infections may be
related to similar mechanisms, Abs specific for IL-13 were used to
neutralize IL-13 in vivo. Neutralizing anti-IL-13 or control Abs
were given i.p. 1 h before intratracheal RSV (3 x
105 PFU) and then every other day thereafter
until day 12 of infection. The mice were examined for changes in airway
hyperreactivity at specific time points after infection (Fig. 4). The mice treated with neutralizing
Abs to IL-13 showed no increase in airway hyperreactivity, whereas
those animals treated with control serum demonstrated significant
changes as described above. In addition, examination of the
bronchoalveolar lavage (BAL) fluid showed a significant difference in
the amount of mucus produced; i.e., the anti-IL-13-treated animals
had almost no mucus in the BAL fluid compared with the RSV controls
(Fig. 5). Interestingly, the
anti-IL-13-treated mice also showed an early and significant rise
in IL-12 (Fig. 6), suggesting that IL-13
produced during the response observed in these experiments may have a
role in down-regulating the Th1-type response. Treatment of mice with
anti-IL-4 had no effect on the development of airway
hyperreactivity during RSV infection (data not shown), corresponding to
the observation of no increase in IL-4 production. Infectious virus
titers peak in lungs of DBA and BALB/c mice at day 4, with no
detectable infectious virus by day 8. We found no difference between
the control and anti-IL-13-treated animals by plaque analysis at
day 4 (data not shown). However, we also examined the RSV-specific Ag
in the lungs by ELISA as an indication of the viral load (Fig. 7). Significant levels of viral Ag (as
represented by ELISA OD readings) was easily detectable at day 4 and
increased by day 8, the time of peak IL-13 production. The
anti-IL-13-treated animals demonstrated significantly lower levels
of viral Ag in their lungs at day 8, suggesting that the virus-specific
protein was cleared more efficiently. Thus, the overproduction of IL-13
during RSV infection may regulate specific responses that are
associated with detrimental pathophysiologic reactions observed within
the infected lungs.
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The activation of specific Th responses, Th1 or Th2, appears to be
regulated by intracellular signal pathways that include STAT protein
activation (25, 26). Specific cytokine ligand binding to
cytokine receptors can activate certain STAT protein pathways. For
example, it has been demonstrated that IL-12 specifically activates
cells via STAT4, whereas IL-4 and IL-13 activate cells via STAT6
(27). Thus, we investigated whether mice genetically
deleted of their STAT6 would respond similarly to mice with Ab
depletions of IL-13. Using mice with a STAT6 deletion, we observed a
significant reduction in peak RSV-induced airway hyperreactivity at
days 8 and 12 postinfection, compared with control mice with an intact
STAT6 pathway (Fig. 8). Interestingly,
IL-13 levels were similar in the STAT6+/+ and
STAT6-/- mice (data not shown), indicating that
STAT6 had a downstream effect on the airway reactivity. These findings
are similar to those obtained in the IL-13 neutralization experiments
with Ab and may provide a basis for describing mechanisms of
RSV-induced airway hyperreactivity.
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This correlates directly with the abrogation of airway hyperreactivity
and the apparent decrease in mucus in the airway. In addition, these
data strongly support the concept that STAT6-mediated pathways induce
production of mucus during inappropriate airway responses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to its role in causing a severe immune response to RSV,
IL-13 may also have an immunomodulatory role. Neutralization of IL-13
allowed the increased production of IL-12, suggesting that IL-13 exerts
a regulatory effect on IL-12 production. Because IL-12 has been linked
to anti-viral responses (35, 36, 37) with RSV as well as
with numerous other viruses, one potential effect of the overproduction
of IL-13 is altered viral clearance related to altered IL-12
production. The persistence of viral Ags within the airway may cause
continued immune responses and damage to the epithelial cell barrier
over long periods, resulting in hyperresponsiveness. This contention is
supported by several studies that showed that prolonged airway
hyperreactivity in RSV-infected animals related directly to the
persistence of virus and its Ags (38, 39, 40). This may be
especially interesting considering that peak viral titers from the
lungs occur around day 4 of infection, whereas the pathophysiologic
responses occur at a later time point. Altered immune response related
to IL-13 regulation of IL-12 correlates with recent studies
demonstrating a decrease in IL-12 in those children who developed
RSV-induced bronchiolitis (41). In these studies, we found
increases in IFN- levels in lung homogenates at earlier time points
that preceded peak airway hyperreactivity. Production of IFN- and
airway hyperreactivity may not be linked in these mice because we found
no alteration in IFN- when we neutralized IL-13 and demonstrated
reduced airway hyperreactivity. Previously, investigators have
identified IFN- production primarily by intracellular cytokine
staining of T lymphocytes or by using higher virus levels for the
challenge (16, 42, 43). It appears that there is a paucity
of IFN- in this system because the addition of exogenous IFN-
significantly protects mice against airway damage and physiologic
alterations (44, 45).
Further complicating the understanding of the precise nature of the immune response to RSV is recent data that has demonstrated that genetic predisposition may play a significant role in the responses to RSV (16, 46, 47). In fact, when examining responses to vaccines directed to RSV, the genetic MHC background of mice directly determined the type of response that was elicited upon rechallenge with virus (16). In these studies, we used mice with a MHC background, H-2d, that responds to RSV in a detrimental way. The results in this study concur directly with those previous findings and suggest that the production of specific cytokines (IL-13 in particular) likely dictates the severity of the RSV response in the lung. In ongoing studies in our laboratory, other genetic strains of mice (H-2b MHC background, C57BL6 mice) have an effective response to RSV and relatively low airway hyperreactivity that centers on high IL-12 and reduced IL-13 (unpublished data). These ongoing studies correlate with original studies concerning IL-12-induced cellular cytotoxicity and viral clearance (48, 49, 50). Thus, the IL-12/IL-13 axis may be central in determining the regulation of the response to RSV and, furthermore, may dictate the severity of the lung dysfunction, which includes airway hyperreactivity, goblet cell hyperplasia, and mucus production. Previous studies that coupled RSV infection with allergic responses indicated that the exacerbation of allergen-induced airway hyperreactivity is associated with RSV-induced IL-5 (4). We found little increase in IL-5 in our studies and few, if any, eosinophils during primary RSV infection. These findings are consistent with previous observations examining primary RSV infections (51, 52). However, because the response was induced via a STAT6 pathway, an overall Th2-type environment may be initiated during the RSV response (24, 26). STAT6 pathways are involved in allergen-induced airway hyperreactivity and mucus production (53, 54). It is likely that multiple factors contribute to the pathophysiology during airway disease, including the genetic background and the cytokine profiles that are generated locally.
Clinically, the attenuation of IL-13 early in disease may have benefits for children who may otherwise go on to have long-term airway reactivity/asthma problems. Several clinical studies have indicated a correlation of decreased IL-12 with severe cases of RSV-induced airway disease (46, 55, 56). These findings, along with a number of animal studies in allergy/asthma, suggest that this cytokine axis may play a significant role in determining the overall direction of the pulmonary response. These results have altogether demonstrated that during a primary RSV infection the regulation of cytokine responses can dictate the airway reactions to RSV. The ability to control the level of IL-13 within the lung may have a notably beneficial effect, not only for the RSV infection, but also for subsequent asthmatic responses within the airway. These and other studies will help to define beneficial and detrimental cytokine responses during RSV infection.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicholas W. Lukacs, Department of Pathology, University of Michigan, 1301 Catherine Road, Ann Arbor, MI 48109-0602.
3 Abbreviations used in this paper: RSV, respiratory syncytial virus; BAL, bronchoalveolar lavage; m, murine; h, human; PAS, periodic acid-Schiff; MIP, macrophage inflammatory protein.
Received for publication June 12, 2000. Accepted for publication December 26, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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M. Chen, K.-F. Hu, B. Rozell, C. Orvell, B. Morein, and P. Liljestrom Vaccination with Recombinant Alphavirus or Immune-Stimulating Complex Antigen Against Respiratory Syncytial Virus J. Immunol., September 15, 2002; 169(6): 3208 - 3216. [Abstract] [Full Text] [PDF]
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 G. Duetsch, T. Illig, S. Loesgen, K. Rohde, N. Klopp, N. Herbon, H. Gohlke, J. Altmueller, and M. Wjst STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study Hum. Mol. Genet., March 1, 2002; 11(6): 613 - 621. [Abstract] [Full Text] [PDF]
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D. M. Walter, J. J. McIntire, G. Berry, A. N. J. McKenzie, D. D. Donaldson, R. H. DeKruyff, and D. T. Umetsu Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity J. Immunol., October 15, 2001; 167(8): 4668 - 4675. [Abstract] [Full Text] [PDF]
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K. K. Tekkanat, H. Maassab, A. A. Berlin, P. M. Lincoln, H. L. Evanoff, M. H. Kaplan, and N. W. Lukacs Role of Interleukin-12 and Stat-4 in the Regulation of Airway Inflammation and Hyperreactivity in Respiratory Syncytial Virus Infection Am. J. Pathol., August 1, 2001; 159(2): 631 - 638. [Abstract] [Full Text]
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N. W. Lukacs, K. K. Tekkanat, A. Berlin, C. M. Hogaboam, A. Miller, H. Evanoff, P. Lincoln, and H. Maassab Respiratory Syncytial Virus Predisposes Mice to Augmented Allergic Airway Responses Via IL-13-Mediated Mechanisms J. Immunol., July 15, 2001; 167(2): 1060 - 1065. [Abstract] [Full Text] [PDF]
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