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3 Inserm U700 and Université Paris 7, Paris, F-75018 France; 4 Laboratoire de Biochimie de la Nutrition, Hôpital Rangueil, Toulouse, F-31059 France; and 5 Antigenics, Lexington, MA 02421-7305
* To whom correspondence should be addressed. E-mail: mpretol{at}bichat.inserm.fr.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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release. These findings demonstrate that, when given during systemic sensitization, Lipo-ATRA exacerbates allergic immune and inflammatory responses, most likely by promoting Th2 development.
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Dietary vitamin A is an essential precursor of retinol, which, in the liver, is either stored as retinyl esters or metabolized by sequential oxidations into all-trans retinoic acid (ATRA). Retinol and ATRA are secreted and transported to target cells associated to retinol-binding protein, lipoproteins, or chylomicrons. In target cells, retinol is oxidized to ATRA, which in turn is reversibly converted to other retinoid acids (RA), 9-cis RA and 13-cis RA (7,8). RA are the biological active metabolites of vitamin A. They interact with 2 groups of receptors, with 3 subtypes (
, ß, and ) for each: the RA receptors (RAR), which mainly bind ATRA and 9-cis RA with high affinity, and the retinoid X receptors (RXR), which bind 9-cis RA but not ATRA (9). The RAR/RXR form homodimers and/or heterodimers that bind to cis-acting response elements of retinoid target genes and interact with a variety of coactivators and repressors (9). Of note, ATRA has a very short half-life in liver and tissues, because it is rapidly catabolized by a specific cytochrome P450, named CYP26, which is induced by ATRA itself (7).
RA regulate cell growth, differentiation, and matrix formation in various cell types and play a major role in the maintenance of a normal epithelial mucociliary phenotype (10,11). Besides their modulatory activities on airway epithelial cells, retinoids suppress eosinophil and basophil differentiation from bone marrow precursors (12), most likely by downregulating the expression of IL-5 receptor on their surface (13), and prevent mitogen-induced proliferation and IL-4-dependent IgE production from murine splenocytes (14,15). However, retinoids also promote in vitro Th2 development both directly, by enhancing transcription of IL-4 by T cells (16,17), and indirectly, by influencing antigen-presenting cell functions (18,19). These in vitro effects of retinoids involve their interaction with either RXR or RAR, or both (14–19). A recent study demonstrated that a selective pan-RXR antagonist given to antigen-sensitized mice during the immunization phase prevented allergic airway inflammation by biasing the immune response in a Th1 direction (20). The possibility that retinoids also control the whole responses (inflammatory and remodeling) to the allergenic challenge remains to be established.
In this study, we examined the effect of pharmacological doses of intraperitoneally (i.p.) injected, liposomally encapsulated ATRA (Lipo-ATRA) in a mouse model of ovalbumin (OVA)-induced asthma manifestations. We used this strategy because it provides advantages over the ATRA oral formulation, notably by circumventing ATRA liver catabolism and clearance (21) and allowing an efficient delivery to target tissues (22,23). To discriminate between potential regulatory effects on primary immune responses and on airway inflammation, Lipo-ATRA was administered either at the time of antigen sensitization or during intrapulmonary antigen challenges. In addition, the ability of ATRA to modulate the synthesis of Th1- and Th2-type cytokines by OVA- and anti-cluster of differentiation (CD)3 antibody (Ab)-stimulated splenocytes and purified spleen CD4+ T lymphocytes was investigated. Finally, because airway remodeling is considered one of the major events involved in asthma severity and chronicity (1), the impact of Lipo-ATRA on antigen-induced extracellular matrix protein deposition and transforming growth factor ß1 (TGFß1) production in the lung was determined.
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Materials and Methods |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Assessment of serum levels of retinoids by HPLC. Naïve mice received a single i.p. injection of 1, 10, or 100 mg/kg Lipo-ATRA containing 10% (wt:wt) ATRA (Antigenics) in 0.2 mL of sterile saline (23) and they were used 1, 2, or 24 h thereafter (Fig. 1, Protocol 1). In the next set of experiments, 100 mg/kg Lipo-ATRA was given as a single i.p. injection 1 h before the first i.p. OVA immunization (Fig. 1, Protocol 2) or before the first i.n. OVA challenge (Fig. 1, Protocol 3) and were used 2 h after Lipo-ATRA administration. All experiments were performed in duplicate. At the selected time points, mice were killed by an i.p. injection of 2.4 g/kg ethyl-carbamate (Sigma) and blood was collected (24). We measured concentrations of serum ATRA, 13-cis RA, and 9-cis RA by HPLC (25) using an Alliance HPLC system with a 2690 separation module and 996 photodiode detector (Waters). The sensitivities were 0.0075 µmol/L for ATRA and 0.0045 µmol/L for both 13-cis RA and 9-cis RA.
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Determination of OVA-specific IgE. The levels of OVA-specific IgE were measured by specific enzyme immunometric assay (26) using a rat anti-mouse IgE monoclonal Ab clone R35–72 (Becton Dickinson). Results were expressed in OD.
Cell counts and distribution in the BAL fluid. Total cell counts were evaluated using a hemocytometer and mononuclear cells, neutrophils, and eosinophils were differentially counted (24).
Mediator assessment in the BAL fluid.
IL-4 was measured in the supernatant of BAL fluid by specific ELISA (24). Recombinant murine IL-4 (R&D Systems Europe) was used to generate standard curves. IL-5, IFN, eotaxin/CCL11, RANTES/CCL5, and TGFß1 were assayed using Quantikine Murine kits (R&D Systems).
We assessed fibronectin release by enzyme immunometric assay (27). Plates were coated with 2 mg/L murine fibronectin (Biogenesis). BAL samples (100 µL) were incubated with a polyclonal rabbit anti-mouse cellular fibronectin Ab (1:5,000; Biogenesis) and then transferred to the fibronectin-coated wells. After washings, excess Ab that did not react with soluble fibronectin was revealed by sequentially adding a biotinylated secondary anti-rabbit IgG (1:25,000; Jackson ImmunoResearch) and the ExtrAvidine peroxidase solution (1:20,000; Sigma). A ready-to-use solution of 3,3', 5,5'-tetramethyl-benzidine (Sigma) was then added for 15 min, the reaction was stopped by adding 20% H2SO4, and the OD was measured at 450 nm.
Mucin levels were measured by a colorimetric assay (28). Plates were coated with serial dilution of the standard type I-S mucin from bovine submaxillary glands (Sigma) or BAL samples diluted at 1:100 for OVA/saline mice or 1:500 for OVA/OVA mice. We then washed, blocked, rewashed, and incubated plates for 1 h at 37°C with biotinylated jacalin (Vector Laboratories). Plates were washed again and mucin-jacalin-biotin complexes were revealed by incubation with ExtrAvidine peroxidase solution (1:40,000). After a final wash, plates were further processed as described above.
Sensitivities were of 7.5 ng/L for IL-4, RANTES/CCL5, and IFN; 15.6 ng/L for IL-5 and eotaxin/CCL11; 31.2 ng/L for TGFß1; 0.5 mg/L for fibronectin; and 500 ng/L for mucin.
Total collagen content in the lung tissue. Total soluble collagen content was determined in homogenates of saline-washed right lung lobes using the Sircol assay (Biocolor). The sensitivity of the assay was 6 µg.
In vitro experiments with isolated splenocytes and purified spleen CD4+ T cells.
Spleen cells from OVA/OVA untreated mice were dispersed using a Dounce homogenizer and erythrocytes were lysed using Mouse Erythrocyte lysing kit (R&D Systems). Whole spleen mononuclear cells were isolated by centrifugation in the Mouse NycoPrep 1.077A separation medium (Axis Shield). CD4+ T lymphocytes were then magnetically enriched using an anti-CD4 monoclonal Ab (clone L3T4; Miltenyi Biotec) as described (29). Whole spleen mononuclear cells (0.375 x 106/200 µL) and CD4+ T lymphocytes (0.2 x 106/200 µL) were cultured as described (29) with or without 100 mg/L OVA. Alternatively, cells were incubated in plates previously coated with 4.5 mg/L of activating anti-CD3 monoclonal Ab (clone 145–2C11; a kind gift of Pr. Michel Goldman) or with its isotype control, i.e. hamster IgG (Becton Dickinson). In both types of experiments, cells were treated with 0.01 and 1 µmol/L ATRA or 9-cis RA (both from Sigma) with their vehicle, i.e. 0.1% dimethylsulfoxide (DMSO) as final concentration or with the medium alone. These concentrations of RA were selected based on previous in vitro studies showing their ability to alter T cell functions (16). After 84 h, plates were centrifuged (80 x g; 5 min, 4°C) and the supernatants were collected and stored at –80°C until the measurements of IL-4, IL-5, and IFN were performed as described above. The cell pellets were incubated at 37°C in a 5% CO2 atmosphere for 4 h with 0.5 g/L of 3,-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (Sigma) in medium, plates were centrifuged, and supernatants were replaced by a solution of 0.04 mol/L HCl in isopropanol. After vigorous stirring, the OD, corresponding to cell number, was 550 nm.
Statistical analysis.
We examined the in vivo effects of OVA challenge, empty liposome injection, and Lipo-ATRA administration on BAL cell number, cytokine, chemokine, TGFß1, fibronectin, and mucin levels in BAL fluids and lung collagen content and the in vitro effects of ATRA and 9-cis RA on cytokine production. Log-transformed values were analyzed using 2-way ANOVA followed by Fisher's protected least significant difference test with StatView SE+Graphics program for Macintosh (Abacus Concepts). P 
0.05 was considered significant. Values are expressed as means ± SEM of the indicated number of mice or cell preparations.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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82% ATRA, 12% of its stereoisomer 13-cis RA, and traces of 9-cis RA. Endogenous ATRA, 13-cis RA, and 9-cis RA were undetectable in the serum of naïve mice (data not shown). A single i.p. injection of 100 mg/kg Lipo-ATRA to nonimmunized mice led to the detection of elevated serum levels of ATRA, 13-cis RA, and 9-cis RA at 1 h (n = 2; Fig. 2A). These levels decreased by >250% at 2 h and became undetectable at 24 h (Fig. 2A). Dose-dependent studies performed at 1 h showed a lower concentration of ATRA following the administration of 10 mg/kg Lipo-ATRA, whereas the levels of 13-cis RA and 9-cis RA were below the detection limit of the assay (n = 2). Neither ATRA nor 13-cis RA or 9-cis RA were detectable 1 h after the i.p. injection of 1 mg/kg Lipo-ATRA to naïve mice (data not shown).
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Effect of Lipo-ATRA on OVA-induced specific IgE production. OVA/OVA empty liposome-treated mice had higher serum levels of OVA-specific IgE compared with OVA/saline empty liposome-treated mice (Fig. 3). Treatment with Lipo-ATRA during challenges did not modify IgE production, whereas administration at the time of sensitization phase resulted in higher levels of IgE in OVA/OVA mice (Fig. 3).
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were below the threshold of the sensitivity of the assay in all groups of mice (data not shown).
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Effect of ATRA on whole splenocytes and purified spleen CD4+ T lymphocyte activation.
OVA-stimulated DMSO-treated splenocytes and anti-CD3-stimulated DMSO-treated CD4+ T cells produced higher amounts of IL-4, IL-5, and IFN than medium- or hamster IgG-stimulated DMSO-treated cells (Table 2). Adding 1 µmol/L ATRA (Table 2) or 9-cis RA (data not shown) to OVA-stimulated splenocytes augmented the levels of IL-4 and reduced those of IFN without modifying IL-5 release. Under the same conditions, ATRA (Table 2) or 9-cis RA (data not shown) increased both IL-4 and IL-5 production and decreased IFN release in anti-CD3-stimulated CD4+ T cells. At 0.01 µmol/L, RA did not alter OVA-induced cytokine production, whereas they significantly reduced IFN release from anti-CD3-stimulated CD4+ T-cells (Table 2). Retinoids did not modulate cytokine levels in medium-stimulated cells (data not shown). Finally, DMSO- or medium-treated cells released similar amounts of cytokines either spontaneously or in response to OVA or anti-CD3 Ab (Table 2).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Using a treatment regimen previously described in mice (23), we demonstrated that, depending on its timing of administration, supraphysiological doses of Lipo-ATRA either exacerbated or altered minimally OVA-induced asthma manifestations. The quasi-absence of effects of Lipo-ATRA in the on challenge protocol is unlikely to be the consequence of OVA i.n. administration on ATRA clearance, because challenge did not alter the levels of circulating ATRA. These results extend those recently reported showing that the administration of a retinoid receptor antagonist during the sensitization phase downregulated antigen-induced allergic airway inflammation (20). The similarities of results between these 2 studies suggest that high doses of Lipo-ATRA are required to achieve physiological concentrations of ATRA at the level of target cells. Indeed, despite ATRA encapsulation into liposomes, a strategy known to limit its clearance, ATRA concentrations rapidly decreased in serum, most probably as a result of its catabolism in the liver and other tissues.
We also noticed that Lipo-ATRA powder used to treat mice contained its natural stereoisomers, 13-cis RA and 9-cis RA, indicating that the effects presently reported result most likely from the activation of both RAR and RXR.
When given at the time of the 2 immunizing injections, Lipo-ATRA upregulated OVA-induced Th2-type responses, including peripheral IgE synthesis, eosinophilia in BAL fluid, and the associated production of IL-5. In contrast, Lipo-ATRA did not modify IgE levels, BAL eosinophilia, and IL-5 release when administered during the 4 i.n. OVA challenges. Using in vitro-cultured splenocytes, we showed that ATRA and 9-cis RA augmented OVA-induced IL-4, but not IL-5, production and decreased the levels of the Th1-type cytokine, IFN. Because RA-mediated inhibition of IFN synthesis may result from a direct effect on the antigen-presenting cells contained in the whole spleen cell populations, experiments were conducted using anti-CD3-stimulated CD4+ T cells. Under these conditions, RA reduced IFN production, increased IL-4 synthesis, and, contrary to the data obtained with OVA-stimulated splenocytes, augmented the levels of IL-5. The similarities of IL-4 and IFN and the discrepancy of IL-5 production by mononuclear splenocytes and purified CD4+ lymphocytes suggest that retinoids alter Th2 responses by modulating the activation of both antigen-presenting cells and T cells. These results corroborate a previous finding showing that retinoids enhance the synthesis of Th2 cytokines and decrease the production of Th1 mediators directly by activating naïve Th0 cells and indirectly by preventing the release of Th1-promoting factors, such as IL-12, by antigen-presenting cells (30). Together, the in vitro and in vivo results showing a shift of RA-treated mononuclear cells toward Th2 phenotype and an upregulation of allergic responses obtained in mice treated with Lipo-ATRA at the time of the 2 systemic sensitizing injections corroborate previous reports demonstrating that in vivo vitamin A dietary supplementation biased the immune response in a Th2 direction, whereas its deficiency shifted this response toward a Th1 phenotype (18,31–33). Supporting these observations, in vivo retinoid treatment improved experimental allergic encephalomyelitis, a Th1-mediated disease in which IL-4 administration delays the onset and reduces the severity (34,35).
The ability of Lipo-ATRA to exacerbate Th2-type responses when given during the immunization phase was accompanied by increased BAL levels of eotaxin/CCL11 and RANTES/CCL5, 2 chemokines that sustain eosinophil homing and accumulation in the airways (4). Of interest, eotaxin/CCL11 and RANTES/CCL5 are produced mainly by the airway epithelium in response to several stimuli, including IL-4 (6,36). However, the finding that Lipo-ATRA is effective on eotaxin/CCL11 and RANTES/CCL5 production only when it is administered at the time of sensitization suggests that, in our model, retinoids influence airway epithelial cell activation, indirectly, through upregulation of Th2-type responses.
To determine the impact of Lipo-ATRA on airway remodeling, we next examined TGFß1, fibronectin, and mucin release in the BAL fluid and collagen deposit in the lung tissue. We found that Lipo-ATRA administration at the time of the immunization phase, but not during intrapulmonary antigen challenges, upregulated OVA-induced TGFß1 and fibronectin generation in the BAL fluid. These results also demonstrated that TGFß1 and fibronectin release, on one hand, and BAL eosinophilia, on the other hand, were similarly modulated by Lipo-ATRA and substantiate previous in vivo observations showing that eosinophils control TGFß1 and fibronectin production in the lung (37–42). It is thus likely that increased TGFß1 and fibronectin production in OVA/OVA Lipo-ATRA-treated mice is the consequence of the upregulation of Th2 responses and the subsequent accumulation and activation of eosinophils in the lungs. Regardless of the treatment regimen, Lipo-ATRA downregulated OVA-induced total soluble collagen accumulation in the lung, suggesting that this phenomenon is independent from the extent of Th2-type responses. In a recent study, ATRA was able to prevent collagen biosynthesis in the mouse lung during bleomycin- and radiation-induced pulmonary fibrosis (43). This effect resulted from a selective inhibition of fibroblast activation, ATRA being ineffective against bronchial epithelial and endothelial cells, 2 other important sources of extracellular matrix proteins in the airways (43). Collectively, these results suggest that Lipo-ATRA may reduce OVA-induced total lung collagen accumulation by inhibiting directly the activation of mesenchymal cells.
Finally, mucus cell metaplasia has been associated with airway eosinophilia in some (38–40) but not all (40) studies and previous reports have established the central role played by IL-4 in this process (44). Here, we provide evidence that OVA-induced mucin release in BAL fluid was similarly augmented by Lipo-ATRA, irrespective of the administration regimen and despite dissimilar modulation of IL-4 release. These findings suggest that these events may be dissociated and that the increased mucus production results from the well-known ability of retinoids to promote epithelial cells differentiation toward a mucociliary phenotype (10,11).
In conclusion, this study demonstrates that the administration of Lipo-ATRA to OVA-immunized mice at the time of antigen sensitization exacerbates IgE synthesis and allergic airway inflammation, whereas it did not substantially alter these responses when given at the time of intrapulmonary OVA challenges. In vitro, RA augmented the synthesis of Th2-type cytokines and reduced the production of IFN from antigen- or anti-CD3-activated splenocytes and spleen CD4+ T lymphocytes, suggesting that Lipo-ATRA aggravates in vivo allergic responses most likely by increasing early Th2 differentiation. Regardless of its administration regimen, Lipo-ATRA reduces lung collagen deposition while it increases mucin production, indicating that Th2-type inflammation, on one hand, and certain features of airway remodeling, on the other hand, are parallel yet independent events in this model. These observations also suggest that the in vivo regulatory properties of retinoids extend to cell types other than immune cells, most likely fibroblasts and airway epithelial cells.
Together, the current results corroborate the hypothesis that targeting retinoid receptors potently modulates Th2-type asthma manifestations in mice. Whether or not diet-derived retinoids are also involved in the development of asthma in humans requires further investigation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosures: M. Maret, C. Ruffie, B. Periquet, A.-M. Campo, M. Menevret, A. Phelep, K. Dziewiszek, A. Druilhe, and M. Pretolan, no conflicts of interest.
6 Present address: Unité des Virus Lents, Institut Pasteur, Paris, F-75015, France.
7 Present address: Centre de Recherche Inserm U845, Equipe "Mécanismes et stratégies thérapeutiques des néphropathies chroniques", Hôpital Necker-Enfants Malades, Paris, F-75015 France.
8 Abbreviations used: Ab, antibody; ATRA, all-trans retinoic acid; BAL, bronchoalveolar lavage; CD, cluster of differentiation; DMSO, dimethylsulfoxide; (eotaxin/CCL11), eotaxin-1/chemokine (C-C motif) ligand 11; i.n., intranasal; i.p., intraperitoneal; Lipo-ATRA, liposomally encapsulated all-trans retinoic acid; OVA, ovalbumin; OVA/OVA, ovalbumin-immunized and ovalbumin-challenged; OVA/saline, ovalbumin-immunized and 0.9% NaCl-challenged; RA, retinoid acid; RANTES/CCL5, regulated upon activation normal T expressed and secreted chemokine (C-C motif) ligand 5; RAR, RA receptor; RXR, retinoid X receptor; saline, 0.9% NaCl; Th, T helper; TGFß1, transforming-growth factor ß1.
Manuscript received 3 April 2007. Initial review completed 18 April 2007. Revision accepted 2 October 2007.
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LITERATURE CITED |
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