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-Mediated Anti-Inflammatory Response in Asthma
Department of Internal Medicine, Airway Remodeling Laboratory, Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, Jeonju, South Korea
Received July 22, 2005; accepted September 1, 2005
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Abstract |
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(PPAR) plays an important role in controlling immune and inflammatory responses. Recent studies have demonstrated that activation of PPAR reduces airway hyper-responsiveness and activation of eosinophils that are increased by induction of asthma. We have used a mouse model of asthma to determine the role of PPAR in the regulation of the pulmonary immune response, more specifically in the involvement of immunoregulatory cytokine interleukin (IL)-10. Administration of PPAR agonists or adenovirus carrying PPAR cDNA (AdPPAR) reduced eosinophilic airway inflammation and airway hyper-responsiveness. Expression of PPAR was increased by ovalbumin inhalation, and the increase was further enhanced by the administration of PPAR agonists or AdPPAR. The increased IL-10 levels in lung tissues after ovalbumin inhalation were further increased by the administration of rosiglitazone, pioglitazone, or AdPPAR. Levels of IL-4, IL-5, and ovalbumin-specific IgE were also increased after ovalbumin inhalation, and the increased levels were significantly reduced by the administration of the PPAR agonists or AdPPAR. The results also showed that inhibition of IL-10 activity with anti-IL-10 receptor antibody partially restored the inflammation. These findings suggest that a protective role of PPAR in the pathogenesis of the asthma is partly mediated through an IL-10-dependent mechanism.
). Among them, PPAR was originally characterized as a regulator of adipocyte differentiation and lipid metabolism (Tontonoz et al., 1994). However, accumulating evidence indicates that PPAR affects cell cycle, differentiation, and apoptosis (Chinetti et al., 1998). In addition, PPAR activation down-regulates synthesis and release of immunomodulatory cytokines from various cell types (Chinetti et al., 1998; Ricote et al., 1998; Gelman et al., 1999). Previous studies have demonstrated that activation of PPAR reduces airway hyperresponsiveness and activation of eosinophils that are increased by induction of asthma (Woerly et al., 2003; Honda et al., 2004; Lee et al., 2005).
Asthma is a chronic inflammatory disorder of the airways in which many cell types play a role (Bousquet et al., 2000). Eosinophil response seems to be a critical feature in asthma (Frigas and Gleich, 1986). Eosinophils play an effector role by release of proinflammatory mediators, cytotoxic mediators, and cytokines, resulting in vascular leakage, hypersecretion of mucus, smooth muscle contraction, epithelial shedding, and bronchial hyper-responsiveness. These cells are also involved in the regulation of the airway inflammation and in the initiation of the remodeling process by the release of cytokines and growth factors. IL-10 is a regulatory cytokine produced by several cell types and exhibits antiallergic inflammatory properties (Hobbs et al., 1998; Moore et al., 2001). IL-10 down-regulates IL-4 and IL-5 expression by T-helper type 2 cell lymphocytes and inhibits eosinophil survival and IgE synthesis (Del Prete et al., 1993; Punnonen et al., 1993; Takanaski et al., 1994). However, inter-relationship between PPAR and IL-10 in regulation of anti-inflammatory function in asthma is not clearly understood.
In the present study, we have used a murine model for asthma to determine the role of PPAR in the regulation of the pulmonary immune response, more specifically in the involvement of IL-10.
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Materials and Methods |
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; Lee et al., 2004). On days 21, 22, and 23 after the initial sensitization, the mice were challenged for 30 min with an aerosol of 3% (w/v) ovalbumin in saline (or with saline as a control) using an ultrasonic nebulizer (NE-U12, Omron Corp., Tokyo, Japan).
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Vectors. The E1/E3-deleted replication-deficient recombinant adenovirus was made using the AdEasy system (Quantum Biotech, Montreal, Canada) described by He et al. (1998). KpnI-XhoI restriction fragments from pcDNA3/wild-type PPAR cDNA were ligated into KpnI-XhoI–digested pShuttleCMV. To create AdLacZ, a SalI-NotI restriction fragment from pcDNA3.1/LacZ (Invitrogen, San Diego, CA) was ligated to SalI-NotI–digested pShuttleCMV. Recombination into the pAAdEasy-1 viral backbone was accomplished in bacteria (Escherichia coli, strain BJ5183, recA-deficient) according to the manufacturer's instructions. The recombination was verified, and the adenoviral recombinant DNA was transferred to a regular strain E. coli (DH5
) that generated far greater yields of DNA. Recombinant pAdEasy plasmids containing CMV-cDNA inserts were purified over QIAGEN columns (Qiagen Inc., Valencia, CA), and 5 µg of PacI-digested DNA was used to transfect QBI-293A cells using the calcium phosphate method (Promega, Madison, WI). Cells were seeded at 2 x 106 cells per 150-mm culture dish at 24 h before transfection. Lysis of transfected cells indicating adenoviral growth occurred within 4 days. After amplification, lysates containing clonal recombinant adenovirus were prepared from 150-mm culture dishes and purified by CsCl gradient centrifugation. Recovered virus was aliquoted and stored at -20°C in 5 mM Tris buffer, pH 8.0, containing 50 mM NaCl, 0.05% bovine serum albumin, and 25% glycerol. Virus was titrated by serial dilution infection of QBI-293A cells, and plaques were counted under an overlay of 0.3% agarose, 10% fetal bovine serum, and 1x Dulbecco's modified Eagle's medium.
Administration of Rosiglitazone, Pioglitazone, GW9662, Ad Vectors, Anti-IL-10 Receptor Antibody, and Isotype Control Monoclonal Antibody. Rosiglitazone (5 mg/kg body weight/day; GlaxoSmithKline, Uxbridge, Middlesex, UK) dissolved in distilled water or pioglitazone (10 mg/kg body weight/day; Takeda Chemical Industries Ltd., Osaka, Japan) dissolved in dimethyl sulfoxide and diluted with 0.9% NaCl, was administered seven times by oral gavage at 24-h intervals on days 19 to 25, beginning 2 days before the first challenge (Fig. 1). GW9662 (0.5 mg/kg body weight/day; Cayman Chemical, Ann Arbor, MI) dissolved in phosphate-buffered saline, was administered intratracheally to each animal twice, once on day 21 and the second time on day 25 (Fig. 1). Anti-IL-10 receptor antibody or isotype control mAb (12.5 mg/kg body weight/day; BD Pharmingen, San Diego, CA) was administered intraperitoneally to each animal twice, once on day 23 (1 h after the last airway challenge with ovalbumin) and the second time on day 24 (24 h after the last airway challenge with ovalbumin) (Fig. 1). Adenoviral vectors were administered intratracheally (109 plaque-forming units) to each animal twice, once on day 21 (1 h before the first airway challenge with ovalbumin) and the second time on day 23 (3 h after the last airway challenge with ovalbumin) (Fig. 1).
Measurement of Cytokines. Levels of IL-4 and IL-5 were quantified in the supernatants of BAL fluids by enzyme immunoassays according to the manufacturer's protocol (Pierce Endogen, Rockford, IL). Sensitivities for IL-4 and IL-5 assays were 5 pg/ml.
Analysis of Ovalbumin-Specific IgE. Ovalbumin-specific IgE levels were measured by capture enzyme-linked immunosorbent assay as described previously (MacLean et al., 2000). Microtiter plates were coated with a purified anti-mouse IgE mAb (BD Pharmingen). To detect ovalbumin-specific IgE, diluted serum samples were added to each well, and the plates were incubated for 2 h at room temperature. After washing five times, biotinylated ovalbumin (10 µg/ml) and horseradish peroxidase (HRP)-conjugated streptavidin were added to each well. Plates were washed, and 3,3'5,5'-tetramethyl-benzidine substrate was added. After incubation for 30 min in the dark at room temperature, the plates were read at 450 nm using a microplate reader (Molecular Dynamics, Sunnyvale, CA).
Western Blot Analysis. Lung tissues were homogenized in the presence of protease inhibitors to obtain extracts of proteins. Protein concentrations were determined using the Bradford reagent (Bio-Rad, Hercules, CA). Samples (30 µg of protein per lane) were loaded on a 12% SDS-polyacrylamide gel electrophoresis gel. After electrophoresis at 120 V for 90 min, separated proteins were transferred to polyvinylidene difluoride membranes (GE Healthcare, Little Chalfont, Buckinghamshire, UK) by the wet transfer method (250 mA, 90 min). Nonspecific sites were blocked with 5% nonfat dry milk in Tris-buffered saline containing Tween 20 (TBST; 25 mM Tris, pH 7.5, 150 mM NaCl, and 0.1% Tween 20) for 1 h, and the blots were then incubated with an anti-IL-10 antibody (MBL International Corporation, Woburn, MA), anti-IL-4 antibody (Serotec Ltd., Oxford, UK), or anti-IL-5 antibody (Santa Cruz Biotechnology, Santa Cruz, CA), overnight at 4°C. Anti-rabbit or anti-mouse HRP conjugated IgG was used to detect binding of the antibody. The membranes were stripped and reblotted with anti-actin antibody (Sigma-Aldrich) to verify equal loading of protein in each lane. The binding of the specific antibody was visualized by exposing to photographic film after treating with enhanced chemiluminescence system reagents (GE Healthcare).
Determination of Airway Responsiveness. Airway responsiveness was also assessed as a change in airway function after challenge with aerosolized methacholine via airways, as described elsewhere (Takeda et al., 1997; Eum et al., 2003). Anesthesia was achieved with 80 mg/kg of pentobarbital sodium injected intraperitoneally. The trachea was exposed through midcervical incision, tracheostomy was performed, and an 18-gauge metal needle was inserted. Mice were connected to a computer-controlled small animal ventilator (flexiVent, SCIREQ, Montreal, Canada). The mouse was quasi-sinusoidally ventilated with nominal tidal volume of 10 ml/kg at a frequency of 150 breaths/min and a positive end-expiratory pressure of 2 cm of H2O to achieve a mean lung volume close to that during spontaneous breathing. This was achieved by connecting the expiratory port of the ventilator to water column. Methacholine aerosol was generated with an in-line nebulizer and administered directly through the ventilator. To determine the differences in airway response to methacholine, each mouse was challenged with methacholine aerosol in increasing concentrations (2.5–50 mg/ml in saline). After each methacholine challenge, the data of airway resistance (RL) was continuously collected. Maximum values of RL were selected to express changes in airway function, which was represented as a percentage change from baseline after saline aerosol.
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). A value of 0 was adjudged when no inflammation was detectable, a value of 1 for occasional cuffing with inflammatory cells, a value of 2 for most bronchi or vessels surrounded by a thin layer (one to five cells) of inflammatory cells, and a value of 3 when most bronchi or vessels were surrounded by a thick layer (more than five cells) of inflammatory cells.
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. Lungs were removed and homogenized in 8 volumes of a lysis buffer containing 1.3 M sucrose, 1.0 mM MgCl2, and 10 mM potassium phosphate buffer, pH 7.2. The homogenate was filtered through four layers of gauze and centrifuged at 1000g for 15 min. The resulting pellets were carefully recovered and resuspended in 2.4 M sucrose, 1.0 mM MgCl2, and 10 mM potassium phosphate buffer, pH 7.2, to maintain a final 2.2 M sucrose concentration and centrifuged at 100,000g for 1 h. The resulting nuclear pellets were washed once with a solution containing 0.25 M sucrose, 0.5 mM MgCl2, and 20 mM Tris-HCl, pH 7.2, and centrifuged at 1000g for 10 min. The pellets were solubilized with a solution containing 50 mM Tris-HCl, pH 7.2, 0.3 M sucrose, 150 mM NaCl, 2 mM EDTA, 20% glycerol, 2% Triton X-100, 2 mM phenylmethylsulfonyl fluoride, and protein inhibitor cocktails. The mixture was kept on ice for 2 h with gentle stirring and centrifuged at 12,000g for 30 min. The resulting supernatant was used as solubilized nuclear proteins for detection of PPAR.
For Western analysis, samples (30 µg of protein per lane) were loaded on a 10% SDS-PAGE gel. After electrophoresis at 120 V for 90 min, separated proteins were transferred to polyvinylidene difluoride membranes (GE Healthcare) by the wet transfer method (250 mA, 90 min). Nonspecific sites were blocked with 5% nonfat dry milk in TBST (25 mM Tris, pH 7.5, 150 mM NaCl, 0.1% Tween 20) for 1 h, and the blots were then incubated with antibody against PPAR (Santa Cruz Biotechnology), overnight at 4°C. Anti-mouse HRP conjugated IgG was used to detect binding of the antibody. The membranes were stripped and reblotted with anti-actin antibody (Sigma-Aldrich) to verify equal loading of protein in each lane. The binding of the specific antibody was visualized by exposing to photographic film after treating with enhanced chemiluminescence system reagents (GE Healthcare).
Densitometric Analyses and Statistics. All immunoreactive and phosphorylation signals were analyzed by densitometric scanning (Gel Doc XR; Bio-Rad Laboratories). Data were expressed as mean ± S.E.M. Statistical comparisons were performed using oneway analysis of variance followed by Fisher's test. Significant differences between groups were determined using the unpaired Student's t test. Statistical significance was set at p < 0.05.
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Results |
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Agonists Increase PPAR Levels in Lung Tissues of Ovalbumin-Sensitized and -Challenged Mice. Western blot analysis revealed that PPAR levels were increased significantly at 60 h after ovalbumin inhalation compared with the levels after saline inhalation (Fig. 2). The increased PPAR levels in lung tissues at 60 h after ovalbumin inhalation were further increased by the administration of rosiglitazone or pioglitazone.
Effect of Rosiglitazone, Pioglitazone, Adenovirus Carrying PPAR cDNA, or GW9662 Plus Rosiglitazone on IL-10 Protein in Lung Tissues of Ovalbumin-Sensitized and -Challenged Mice. Western blot analysis showed that IL-10 levels were increased significantly at 60 h after ovalbumin inhalation compared with the levels after saline inhalation (Fig. 3). The increased IL-10 levels in lung tissues at 60 h after ovalbumin inhalation were further increased by the administration of rosiglitazone, pioglitazone, or AdPPAR, whereas the rosiglitazone-mediated increase of IL-10 level was blocked by a PPAR antagonist, GW9662 (Fig. 3).
Effect of Rosiglitazone, Pioglitazone, AdPPAR, GW9662 Plus Rosiglitazone, or Anti-IL-10 Receptor Antibody with Rosiglitazone on Cellular Changes in BAL Fluids. Numbers of total cells and eosinophils were increased significantly at 60 h after the last ovalbumin challenge compared with levels after saline inhalation (Fig. 4). The increased numbers of total cells and eosinophils in BAL fluids at 60 h after the last ovalbumin challenge were significantly reduced by the administration of rosiglitazone, pioglitazone, or AdPPAR. The inhibitory effect of rosiglitazone treatment on numbers of eosinophils in BAL fluids was abrogated when a PPAR antagonist, GW9662, was administered concomitantly with the agonist. These results indicate that rosiglitazone was mainly acting through PPAR in this model. The inhibitory effect of rosiglitazone treatment significantly restored the BAL eosinophilia when anti-IL-10 receptor antibody was administered concomitantly with rosiglitazone, but the restoration of the eosinophilia was not observed after the administration of isotype control mAb with rosiglitazone, suggesting that the effects induced by PPAR agonist were partly mediated through an IL-10-dependent mechanism.
Effect of Rosiglitazone or Anti-IL-10 Receptor Antibody Plus Rosiglitazone on Pathological Changes of Ovalbumin-Induced Asthma. Histologic analyses revealed typical pathologic features of asthma in the ovalbumin-exposed mice. Numerous inflammatory cells, including eosinophils, infiltrated around the bronchioles, and the airway epithelium was thickened (Fig. 5B) compared with the control (Fig. 5A). Mice treated with rosiglitazone (Fig. 5C), showed marked reductions in the thickening of airway epithelium, in the infiltration of inflammatory cells in the peribronchiolar region, and in the number of inflammatory cells. The inhibitory effect of rosiglitazone treatment on typical pathologic features of asthma in the ovalbumin-exposed mice was partially abrogated when anti-IL-10 receptor antibody was administered concomitantly with rosiglitazone (Fig. 5D).
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Effect of Rosiglitazone, Pioglitazone, GW9662 Plus Rosiglitazone, Anti-IL-10 Receptor Antibody Plus Rosiglitazone, or AdPPAR on IL-4 and IL-5 in Lung Tissues and BAL Fluids of Ovalbumin-Sensitized and -Challenged Mice. Western blot analysis revealed that IL-4 and IL-5 protein levels in lung tissues were increased significantly at 60 h after ovalbumin inhalation compared with the levels after saline inhalation (Fig. 6A). The administration of rosiglitazone, pioglitazone, or AdPPAR reduced significantly the increased IL-4 and IL-5 levels at 60 h after ovalbumin inhalation, whereas GW9662 plus rosiglitazone or anti-IL-10 receptor antibody plus rosiglitazone did not. Consistent with the results obtained from the Western blot analysis, enzyme immunoassays showed that levels of IL-4 and IL-5 in BAL fluids were increased significantly at 60 h after ovalbumin inhalation compared with the levels after saline inhalation. The administration of rosiglitazone, pioglitazone, or AdPPAR reduced significantly the increased IL-4 and IL-5 levels at 60 h after ovalbumin inhalation, whereas GW9662 plus rosiglitazone or anti-IL-10 receptor antibody plus rosiglitazone did not (Fig. 6B).
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Effect of Rosiglitazone, Pioglitazone, GW9662 Plus Rosiglitazone, Anti-IL-10 Receptor Antibody Plus Rosiglitazone, or AdPPAR on Ovalbumin-Specific IgE Levels in Sera of Ovalbumin-Sensitized and -Challenged Mice. Enzyme immunoassays revealed that levels of ovalbumin-specific IgE in sera were increased significantly at 60 h after ovalbumin inhalation compared with the levels after saline inhalation. The administration of rosiglitazone, pioglitazone, or AdPPAR reduced significantly the increased ovalbumin-specific IgE levels at 60 h after ovalbumin inhalation, whereas GW9662 plus rosiglitazone or anti-IL-10 receptor antibody plus rosiglitazone did not (Fig. 7).
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, or Anti-IL-10 Receptor Antibody on Airway Hyper-Responsiveness. Airway responsiveness was assessed as a percentage increase of RL in response to increasing doses of methacholine. In ovalbumin-sensitized and -challenged mice, the dose-response curve of RL shifted to the left compared with that of control mice (Fig. 8A). In addition, the RL produced by methacholine administration (at doses from 2.5 to 50 mg/ml) increased significantly in the ovalbumin-sensitized and -challenged mice compared with the control mice. Ovalbumin-sensitized and -challenged mice treated with rosiglitazone, pioglitazone, or AdPPAR showed a dose-response curve of RL that shifted to the right compared with that of untreated mice or ovalbumin-sensitized and -challenged mice treated with AdLacZ. These results indicate that rosiglitazone, pioglitazone, or AdPPAR treatment reduces ovalbumin-induced airway hyper-responsiveness. The inhibitory effect of rosiglitazone treatment on airway hyper-responsiveness was abrogated when GW9662 was administered concomitantly with the agonist.
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The reduced value of RL after the administration of rosiglitazone was increased significantly when anti-IL-10 receptor antibody was administered concomitantly with rosiglitazone (Fig. 8B). These findings suggest that the effect induced PPAR agonist on airway hyper-responsiveness were partly mediated through an IL-10-dependent mechanism.
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Discussion |
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). Protein interactions play an important role in the actions of PPARs. In the inactivated state, nuclear receptors such as PPARs are considered complexes bound with corepressor proteins. Upon ligand activation, PPARs dissociate from corepressors and recruit coactivators, including the PPAR-ligand protein and the steroid receptor coactivator-1, which can translocate from the cytoplasm to the nucleus (Zhu et al., 1996, 1997; Bishop-Bailey and Hla, 1999). Among PPARs, PPAR plays an important role in anti-inflammatory responses (Chinetti et al., 1998; Jiang et al., 1998; Ricote et al., 1998; Gelman et al., 1999). Recent studies have demonstrated that activation of PPAR reduces expression of various cytokines, airway hyper-responsiveness, and activation of eosinophils, which are all increased by induction of asthma (Woerly et al., 2003; Honda et al., 2004; Lee et al., 2005). IL-10 is an anti-inflammatory cytokine that down-regulates cellular immunity and allergic inflammation. However, inter-relationship between these proteins in the pathogenesis of the asthma has not been clarified. Our present study with ovalbumin-induced murine model of asthma has revealed that activation of PPAR with the agonists enhances expression of PPAR, resulting in reduction of eosinophilic inflammation and airway hyper-responsiveness. The increased IL-10 levels in lung tissues after ovalbumin inhalation are further increased by the administration of rosiglitazone, pioglitazone, or AdPPAR. In addition, inhibition of IL-10 activity with anti-IL-10 receptor antibody partially restores the inflammation. These findings suggest that a protective role of PPAR in the pathogenesis of the asthma is partly mediated through an IL-10-dependent mechanism.
Thiazolidinediones such as rosiglitazone and pioglitazone are high-affinity ligands for PPAR and are used as insulin-sensitizing drugs in type 2 diabetes mellitus (Lehmann et al., 1995). PPAR is originally known to regulate adipocyte differentiation and lipid metabolism (Tontonoz et al., 1994). Previous studies have demonstrated that PPAR may be involved in airway inflammation and airway hyper-responsiveness in asthma (Woerly et al., 2003; Honda et al., 2004; Lee et al., 2005). Consistent with these observations, our results have shown that administration of the PPAR agonists or AdPPAR substantially inhibits expression of cytokines (IL-4 and IL-5), airway hyper-responsiveness, and eosinophilic inflammation. Moreover, induction of asthma through ovalbumin challenge increases expression of PPAR itself and administration of the agonists further enhances the receptor expression. Up-regulation of PPAR expression has also been observed in human asthmatic airways (Benayoun et al., 2001). Overexpression of PPAR by administration of AdPPAR results in reduction of all asthmatic features in our ovalbumin-induced murine model of asthma. These findings indicate that PPAR is associated with anti-inflammatory responses in asthma.
The role of IL-10 as an anti-inflammatory cytokine in allergic inflammation has been reported (Borish, 1998). Administration of IL-10 has been shown to abrogate allergen-induced airway inflammation (Zuany-Amorim et al., 1995), and IL-10 down-regulates IL-4 and IL-5 expression by T-helper type 2 lymphocytes (Takanaski et al., 1994). Consistent with the observations, IL-10 knockout mice develop a lethal form of allergic bronchopulmonary aspergillosis with markedly elevated expression of IL-4 and IL-5 (Grunig et al., 1997). A modulating role of IL-10 in human allergic diseases is also observed (Punnonen et al., 1993; Takanaski et al., 1994). IL-10 inhibits eosinophil survival and IgE synthesis. Although regulation mechanism of IL-10 synthesis has not been clarified, previous studies have shown that production of IL-10 is increased by treatment with a selective PPAR agonist or tetradecylthioacetic acid, known as a PPAR ligand (Aukrust et al., 2003; Hammad et al., 2004). Hammad et al. (2004) suggest that PPAR agonist-treated dendritic cells can induce the generation of a population of IL-10-producing T cells that could suppress some of the features of asthma. Consistent with these observations, our studies with the ovalbumin-induced asthma model show that enhanced levels of IL-10 in lung tissues after ovalbumin inhalation are further increased by the administration of the PPAR agonists (rosiglitazone and pioglitazone) or AdPPAR. We have also found that the administration of the PPAR agonists or AdPPAR reduces significantly the increased levels of IL-4 and IL-5, including the levels of ovalbumin-specific IgE synthesized by the ovalbumin inhalation. In addition, it seems that production of IL-10 induced by ovalbumin inhalation is physiologically relevant as an inhibitory signaling of asthma, because the blocking antibody, anti-IL-10 receptor antibody, partially restores inflammatory features of asthma. However, Lytle et al. (2005) have shown that rosiglitazone has anti-inflammatory effect independent of IL-10 in a animal model of inflammatory bowel disease. Although the reason is not clearly understood, the discrepancy may be due to the disease model of animal (inflammatory bowel disease versus asthma).
In conclusion, our results have demonstrated that administration of the PPAR agonists or AdPPAR may improve the asthmatic features via regulation of IL-10 expression/IL-10 receptor activation. Hence, PPAR agonist may have therapeutic potential for the treatment of airway inflammation and hyper-responsiveness.
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Acknowledgements |
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Footnotes |
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S.R.K. and K.S.L. contributed equally to this work.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; IL, interleukin; BAL, bronchoalveolar lavage; GW9662; mAb, monoclonal antibody; HRP, horseradish peroxidase; TBST, Tris-buffered saline/Tween 20; RL, airway resistance; AdPPAR, adenovirus carrying PPAR cDNA.
Address correspondence to: Dr. Yong Chul Lee, Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keumamdong, Jeonju, 561-712, South Korea. E-mail: leeyc{at}chonbuk.ac.kr
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, p < 0.05 versus OVA+ROSI.
