All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma
© Wu et al.; licensee BioMed Central Ltd. 2013
Received: 18 December 2012
Accepted: 18 June 2013
Published: 22 June 2013
Airway inflammation is mainly mediated by T helper 2 cells (Th2) that characteristically produce interleukin (IL)-4, IL-5, and IL-13. Epidemiological studies have revealed an inverse association between the dietary intake of vitamin A and the occurrence of asthma. Serum vitamin A concentrations are significantly lower in asthmatic subjects than in healthy control subjects. It has been reported that all-trans retinoic acid (ATRA), a potent derivative of vitamin A, regulates immune responses. However, its role in Th2-mediated airway inflammation remains unclear. We investigated the effects of ATRA in a mouse model of allergic airway inflammation.
We found that ATRA treatment attenuated airway inflammation and decreased mRNA levels of Th2- and Th17-related transcription factors. The data showed that airway inflammation coincided with levels of Th2- and Th17-related cytokines. We also showed that ATRA inhibited Th17 and promoted inducible regulatory T-cell differentiation, whereas it did not induce an obvious effect on Th2 differentiation in vitro. Our data suggest that ATRA may interfere with the in vivo Th2 responses via T-cell extrinsic mechanisms.
Administration of ATRA dramatically attenuated airway inflammation by inhibiting Th2 and Th17 differentiation and/or functions. ATRA may have potential therapeutic effects for airway inflammation in asthmatic patients.
KeywordsAsthma All-trans retinoic acid Th2 Th17 Regulatory T cells
Epidemiological studies have reported an inverse association between asthma and the intake of vitamin A. Dietary vitamin-A intake and serum vitamin-A concentrations are significantly lower in patients with asthma than in healthy control subjects or in people with severe asthma than in those with mild asthma [1–3]. All-trans retinoic acid (ATRA) is a biologically active metabolite of vitamin A with profound effects on T-cell activation [4, 5], differentiation , and function [7, 8]. ATRA binds to retinoic acid receptors in the nucleus leading to the activation of transcription of many target genes [9–11]. Emerging evidence demonstrates that ATRA signaling is critical for T cells differentiation and function. ATRA is an early mediator in the development of CD4+ T cell-mediated immunity, and also plays a pivotal role in optimal effector and effector memory CD8+ T cell differentiation in which vitamin A supplementation is used to augment effector responses [12, 13]. Meanwhile, ATRA promotes Foxp3+ regulatory T-cell (Treg) differentiation and sustains the stability and function of natural Tregs in an inflammatory milieu. In addition, it suppresses Th17 differentiation. ATRA and rapamycin can synergistically increase TGF-β-mediated Foxp3 induction in antigen-specific Th2 memory cells when effector cytokines are neutralized. These Foxp3+ T cells converted from Th2 memory cells possess Treg activity and can ameliorate Th2 memory-mediated airway hyperreactivity and eosinophilic inflammation [14–20]. Moreover, ATRA suppresses Th2-related chemokine expression in vitro by down-regulating the expression of interleukin (IL)-5 receptor and inhibiting eosinophil and basophil differentiation [21–23]. In addition to modulating T cells, ATRA plays an important role in the maintenance of the normal epithelial mucociliary phenotype . However, the role of ATRA on airway inflammation after allergenic challenge has not been established. The goal of this study is to determine whether ATRA alters Th2 response to modulate the severity of airway inflammation in an ovalbumin (OVA)-induced allergic airway inflammation animal model.
Administration of ATRA attenuated lung inflammation
Administration of ATRA decreased the levels of Th2 and Th17-related cytokines, and down-regulated the expression of corresponding transcription factors in the lung
Administration of ATRA suppressed the levels of Th2 and Th17-related cytokines in draining lymph nodes
In-vivo ATRA treatment inhibited Ag-specific Th2 responses with no obvious effect on Foxp3+ Treg population in the spleen
Retinoic acid does not obviously affect Th2 differentiation in vitro
Previous reports showed that ATRA is the biological active metabolite of vitamin A and has an important immunomodulatory effect by inhibiting Th17 polarization and enhancing Foxp3 expression [14–16]. By using a murine Th2-mediated airway inflammation model, we demonstrated that the administration of ATRA attenuated OVA-induced airway inflammation by decreasing Th2 and Th17 related cytokines and inflammatory cells in the airway and ATRA mediated reduction of Th2 cytokines was via inhibiting GATA-3 expression. Our findings provide further supports for the anti-inflammatory role of ATRA in the treatment of lung diseases.
OVA-induced allergic asthma is recognized as a pathological condition that results from chronic airway inflammation characteristically associated with the infiltration of lymphocytes, eosinophils, macrophages, and neutrophils into the bronchial lumen. An aberrant Th2-type response to allergens is characterized by the overproduction of IL-4, IL-5, and IL-13, which are critical for the maintenance of ongoing IgE-mediated eosinophilic inflammation [24–26]. Accumulating evidence has suggested that aberrant IL-17 production is a key determinant of severe forms of asthma. IL-17A induces lung-structural cells to secrete proinflammatory cytokines (TNF, IL-1β, granulocyte colony-stimulating factor, and IL-6) and chemokines (CXCL1, CXCL2, and CXCL8/IL-8), thereby triggering neutrophil infiltration [27–29].
We showed that the administration of ATRA inhibited OVA mediated secretion of IL-4 and IL-5 in the lung, draining lymph nodes, and the spleen. Consistent with the decreased levels of Th2-related cytokines, the recruitment of inflammatory cells, especially eosinophils, neutrophils, lymphocytes, and macrophages, was markedly decreased in the BALF and the lung after ATRA administration. These results indicated that ATRA may alleviate airway inflammation by reducing Th2 cytokines. Meanwhile, T-bet and GATA-3 are responsible for the regulation of the cytokine genes during Th1/Th2 differentiation. GATA-3 has been shown to promote the expression of several Th2 cytokines, including IL-4, IL-5, and IL-13 [30, 31]. It is well known that overexpression of GATA-3 predisposes for Th2-mediated diseases such as allergic asthma and suppression of GATA-3 expression in the lung reduces IL-4, IL-5, and IL-13 productions concurrently [30, 31]. Compared with the vehicle group, the GATA-3 mRNA level in the lung in the ATRA treated group was significantly decreased, which may partially explain the reduction of IL-4 and IL-5 production in these mice. In addition, a recent study performed in chronic asthma model showed that prolonged ATRA treatment tends to inhibit Th17 cell infiltration and neutrophilia without obvious alteration of Th2 cell numbers . The different observations are probably due to different Th-dominate asthma models used between the two studies, in which the immune responses are mediated by different Th subsets.
The concentration of retinoic acid is likely to be critical to its effect on the airway responses. Previous studies have demonstrated that ATRA reverses the airway hyperresponsiveness (AHR) and exogenous administration of retinoic acid is capable of attenuating the asthma phenotype [32–34]. However, it has also been reported that ATRA promotes Th2 development to exacerbate allergic immune and inflammatory responses during systemic sensitization . The differences in the responses of the airway are probably linked to the different concentrations and time point used in those studies. Indeed, the study performed by Mateu et al. supports the above notion. They have found that retinoic acid directly enhances allergic responses in vivo, but higher doses effectively decrease AHR by inhibiting IL-5 production . Therefore, the concentration and time point of retinoic acid should be carefully considered in the applications.
Of note, ATRA was not able to affect Th2 differentiation in a Th2 skewing condition in vitro. The discrepancy between the effects of ATRA on in-vitro and in-vivo Th2 responses suggested that ATRA might not intrinsically control Th2 differentiation. Rather, it might do so by inhibiting the Th17 response or by modulating the function of antigen presenting cells. In addition, Bidad K et al. have reported that ATRA can significantly decrease Th17 cells in patients with ankylosing spondylitis. The effect of ATRA in such patients serves as an immunomodulator on deviated immune cells, which is associated with decreased inflammatory cytokine TNF-α secretion . In our study, we also found that the level of IL-17A was slightly decreased in the draining lymph nodes and lung, while IFN-γ and T-bet mRNAs were slightly increased in the lung after the administration of ATRA. Unlike the in-vitro results previously reported by Elias et al. , our in vivo data showed that ATRA moderately increased IL-10 expression without affecting IL-10 production, Foxp3 expression and Treg numbers in the lung or spleen. The different responses of Treg cells might be attributed to the difference between the in-vivo environment and in-vitro condition . Additionally, ATRA effects on Treg cells in vivo might be also influenced by the exposure time of ATRA. For example, Zhao et al. found that the proportion of Foxp3+ CD4 Treg cells in the lymph nodes is temporarily increased after a week of ATRA treatment . The data suggest that ATRA may affect Treg cells in a context- and time-dependent manner.
In summary, ATRA administration significantly decreased Th2- and Th17-related cytokines and markedly reduced airway inflammation in a murine allergic airway inflammation model. These findings suggested that ATRA may serve as an effective therapy for allergic airway inflammation. Our study suggested potential benefits of Vitamin-A supplement for asthma patients and may provide the basis for further investigation of the mechanisms underlying the potential therapeutic effects of ATRA or vitamin A in controlling the airway inflammation of asthma.
A total of 90 female BALB/c mice and 3 DO11.10 mice at 6 ~ 8 weeks of age were purchased from the Shanghai SLAC Laboratory Animal Company. All mice were maintained under specific pathogen-free conditions in our animal facility. BALB/c mice were randomly divided into 3 groups: a control group, OVA plus vehicle (vehicle group), and OVA-plus ATRA (ATRA group). Each group included 10 mice, and 3 independent experiments were performed. Animal experiments were performed according to the Ethics Committee of Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
Ag sensitization and challenge protocol and administration of ATRA
The mouse-asthmatic model was established as described previously [37, 38]. In both vehicle and ATRA groups, mice received i.p. injections of 100 μg OVA (Sigma-Aldrich) in 0.2 ml Al(OH)3 adjuvant suspension on days 0 and 14. On days 14, 25, 26, and 27, mice were anesthethized with isoflurane and intranasally received 100 μg of OVA in 0.05 ml phosphate buffer saline (PBS) (days 14) and 50 μg of OVA in 0.05 ml PBS (days 25, 26, and 27). The control group was sensitized with the same volume of Al(OH)3 and challenged with normal saline instead of OVA. ATRA was dissolved in dimethyl sulfoxide (DMSO) and diluted in corn oil. Mice in the ATRA group received i.p. injections of 400 μg ATRA on days –1, 13, 24, and 26, the latter being one day prior to OVA sensitization. The mice in the vehicle group were injected with the same volume of corn oil.
Bronchoalveolar lavage fluid (BALF)
The lung lobe was fixed in 10% formalin, embedded in paraffin, and sectioned in 4 μm slices. Sections were stained with H&E and examined microscopically.
Detection of soluble cytokine levels in lung
To determine soluble cytokine levels in the lungs, a snap-frozen right lung lobe from each mouse was thawed on ice and homogenized in a buffer containing a protein-protease inhibitor and 0.1% Triton X-100. The samples were centrifuged, and 50 μl of cell-free supernatant was analyzed by ELISA according to the manufacturer’s instructions. Cytokine levels including IL-4, IL-5, interferon (IFN)-γ, IL-10 and IL-17 in the culture supernatants of mediastinal lymph nodes, splenocytes and lung homogenates were quantified. All the antibodies for the assay were purchased from Biolegend.
Cells stimulation and cytokines assay in vitro
Lymphocytes and splenocytes were used to determine the immune-regulatory effects of ATRA. On day 28, the mice were sacrificed and mediastinal lymph nodes and spleens were isolated. The cell clumps were disaggregated into single-cell suspensions using nylon mesh (30 μm) filtration. Red blood cells were removed by a red-blood-cell lysis buffer. The isolated lymphocytes and splenocytes were cultured in a 0.5 ml RPMI 1640 medium (Sigma-Aldrich) supplemented with 2 mmol/L L-glutamine, 10% fetal calf serum (FCS), 100 mg/ml streptomycin, 100 IU/ml penicillin, 10 mm HEPES, and 20 mm sodium hydrogen carbonate (Invitrogen Life Technologies, Carlsbad, California, USA). Lymphocytes and splenocytes were cultured at the density of 2 × 106/ml in 48 well plates under the stimulation with 10 μg/ml OVA323–339 peptide for 72 hours. The cells were harvested and intracellular staining for IFN-γ, IL-4, and IL-17A were performed for flow cytometry. The cell supernatants were collected and analyzed for IFN-γ, IL-4, IL-5, IL-17A, and IL-10 using mouse ELISA kits (Biolegend).
Real-time PCR analysis
For the total RNA isolation, lung tissue was removed from the animal, immediately froze in liquid N2, and stored at –70°C for assaying. The frozen lung tissue was then homogenized in TRIzol reagent (Invitrogen Life Technologies, Carlsbad, California, USA), and the total RNA was isolated according to the manufacturer’s instructions. Reverse transcription was performed using 40 ng of the total RNA with Superscript III RT kit (Qiagen) and oligo(dT) primers (Invitrogen Life Technologies, Carlsbad, California, USA) as recommended by the manufacturer. The Bio-Rad quantitative PCR SYBR Green Master Mix (Bio-Rad Laboratories) was used and performed the following program: 95°C for 5 min and 40 cycles of amplification at 95°C for 15 seconds and 58°C for 60 seconds. Relative levels of target mRNA were compared with β-actin using the 2−ΔΔCt method. Primer sequences were obtained from Integrated DNA Technologies. Sequences were as follows: β-actin Forward: 5′-GGC TGT ATT CCC CTC CAT CG-3′, Reverse: 5′-CCA GTT GGT AAC AAT GCC ATG T-3′; IL-4 Forward: 5′-GGT CTC AAC CCC CAG CTA GT-3′, Reverse: 5′-GCC GAT GAT CTC TCT CAA GTG AT-3′; IL-10 Forward: 5′-GCT CTT ACT GAC TGG CAT GAG-3′, Reverse: 5′-CGC AGC TCT AGG AGC ATG TG-3′; IL-17A Forward: 5′-TTT AAC TCC CTT GGC GCA AAA-3′, Reverse: 5′-CTT TCC CTC CGC ATT GAC AC-3′; IFN-γ Forward: 5′-ATG AAC GCT ACA CAC TGC ATC-3′, Reverse: 5′-CCA TCC TTT TGC CAG TTC CTC-3′; Foxp3 Forward: 5′-CAC AAT ATG CGA CCC CCT TTC-3′, Reverse: 5′-AAC ATG CGA GTA AAC CAA TGG TA-3′.
In-vitro Th2 differentiation assays
Naïve CD4+ T cells were isolated from 3 DO11.10 mice, and a single-cell suspension was prepared by grinding spleen against a 70-μm nylon cell strainer. After lysis of red cells by red-blood-cell lysis buffer, naïve CD4+ T cells (CD4+ CD62Lhigh CD25-) were first purified by a Mouse CD4+ T Cell Isolation Kit (Miltenyi Biotech) and followed by FACS-sorting. Cells were seeded in 48-well plates for further experiments. The seeding density was 2 × 105 naïve T cells/well.
Naïve T cells were maintained in RPMI 1640 (Invitrogen Life Technologies, Carlsbad, CA) supplemented with 2 mmol/L L-glutamine, 10% fetal-calf serum (FCS), 100 mg/ml streptomycin, 100 IU/ml penicillin, 10 mm HEPES, and 20 mm sodium hydrogen carbonate (Invitrogen Life Technologies, Carlsbad, California, USA). The cells were activated with plate-bound anti-CD3 (2 μg/ml), and soluble anti-CD28 (2 μg/ml) antibodies (BD PharMingen). Th-neutral conditions (Th0) contained no exogenous cytokines or anti-cytokines. Th2 conditions contained 10 ng/ml IL-4 (R&D Systems) with 10 μg/ml anti-IFN-γ (BD PharMingen). Where indicated, IL-2 was added at 100 IU/ml. All ATRA (Sigma, St Louis, MO) were dissolved in dimethyl sulfoxide (DMSO) at stock concentrations of 0.01 M and stored at −80°C in light-proof containers. Stocks were thrown away after 4 freeze-thaw cycles. Cultures containing ATRA were protected from light throughout the time of culture; unless stated otherwise, ATRA was used at different concentration from 0.01, 0.05, 0.1, 0.5, 1, 2.5, 5 to 10 μmol/L.
Data are presented as mean ± SEM. The differences between mean values were calculated using student’s t test, and a p value of less than 0.05 was considered significant. All experiments were repeated at least 3 times, and n = 10 in each experimental group.
All-trans retinoic acid
Bronchoalveolar lavage fluid
We thank the flow cytometry core facility at Shanghai Jiaotong University School of Medicine for cell sorting and flow data analyses. This work was supported by grants from the National Natural Science Foundation of China (Grants 81070022, 81128001 and 81270084) and the Shanghai Municipal Science and Technology Commission Foundation (13XD1402800 and 10410701000).
- Allen S, Britton JR, Leonardi-Bee JA: Association between antioxidant vitamins and asthma outcome measures: systematic review and meta-analysis. Thorax. 2009, 64 (7): 610-619. 10.1136/thx.2008.101469.View ArticlePubMedGoogle Scholar
- Al Senaidy AM: Serum vitamin A and beta-carotene levels in children with asthma. J Asthma. 2009, 46 (7): 699-702. 10.1080/02770900903056195.View ArticlePubMedGoogle Scholar
- McGowan SE: Vitamin A deficiency increases airway resistance following C-fiber stimulation. Respir Physiol Neurobiol. 2007, 157 (2–3): 281-289.View ArticlePubMedGoogle Scholar
- Hall JA, Cannons JL, Grainger JR, Dos Santos LM, Hand TW, Naik S, Wohlfert EA, Chou DB, Oldenhove G, Robinson M, Grigg ME, Kastenmayer R, Schwartzberg PL, Belkaid Y: Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity. 2011, 34 (3): 435-447. 10.1016/j.immuni.2011.03.003.PubMed CentralView ArticlePubMedGoogle Scholar
- Ertesvag A, Austenaa LM, Carlsen H, Blomhoff R, Blomhoff HK: Retinoic acid inhibits in vivo interleukin-2 gene expression and T-cell activation in mice. Immunology. 2009, 126 (4): 514-522. 10.1111/j.1365-2567.2008.02913.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Hall JA, Grainger JR, Spencer SP, Belkaid Y: The role of retinoic acid in tolerance and immunity. Immunity. 2011, 35 (1): 13-22. 10.1016/j.immuni.2011.07.002.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang J, Huizinga TW, Toes RE: De novo generation and enhanced suppression of human CD4+CD25+ regulatory T cells by retinoic acid. J Immunol. 2009, 183 (6): 4119-4126. 10.4049/jimmunol.0901065.View ArticlePubMedGoogle Scholar
- Ahmad SM, Haskell MJ, Raqib R, Stephensen CB: Vitamin A status is associated with T-cell responses in Bangladeshi men. Br J Nutr. 2009, 102 (6): 797-802. 10.1017/S0007114509316165.View ArticlePubMedGoogle Scholar
- Zhang XK, Lehmann J, Hoffmann B, Dawson MI, Cameron J, Graupner G, Hermann T, Tran P, Pfahl M: Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature. 1992, 358 (6387): 587-591. 10.1038/358587a0.View ArticlePubMedGoogle Scholar
- Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A: 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature. 1992, 355 (6358): 359-361. 10.1038/355359a0.View ArticlePubMedGoogle Scholar
- Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C: 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992, 68 (2): 397-406. 10.1016/0092-8674(92)90479-V.View ArticlePubMedGoogle Scholar
- Pino-Lagos K, Guo Y, Brown C, Alexander MP, Elgueta R, Bennett KA, De Vries V, Nowak E, Blomhoff R, Sockanathan S: A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J Exp Med. 2011, 208 (9): 1767-1775. 10.1084/jem.20102358.PubMed CentralView ArticlePubMedGoogle Scholar
- Allie SR, Zhang W, Tsai CY, Noelle RJ, Usherwood EJ: Critical role for All-trans retinoic acid for optimal effector and effector memory CD8 T cell differentiation. J Immunol. 2013, 190 (5): 2178-2187. 10.4049/jimmunol.1201945.PubMed CentralView ArticlePubMedGoogle Scholar
- Tsai YC, Chang HW, Chang TT, Lee MS, Chu YT, Hung CH: Effects of all-trans retinoic acid on Th1- and Th2-related chemokines production in monocytes. Inflammation. 2008, 31 (6): 428-433. 10.1007/s10753-008-9095-x.View ArticlePubMedGoogle Scholar
- Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM, O’Shea JJ: Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood. 2008, 111 (3): 1013-1020.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim BS, Kim IK, Park YJ, Kim YS, Kim YJ, Chang WS, Lee YS, Kweon MN, Chung Y, Kang CY: Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma. Proc Natl Acad Sci U S A. 2010, 107 (19): 8742-8747. 10.1073/pnas.0911756107.PubMed CentralView ArticlePubMedGoogle Scholar
- Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F: A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007, 204 (8): 1757-1764. 10.1084/jem.20070590.PubMed CentralView ArticlePubMedGoogle Scholar
- Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y: Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007, 204 (8): 1775-1785. 10.1084/jem.20070602.PubMed CentralView ArticlePubMedGoogle Scholar
- Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ: All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007, 204 (8): 1765-1774. 10.1084/jem.20070719.PubMed CentralView ArticlePubMedGoogle Scholar
- Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H: Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007, 317 (5835): 256-260. 10.1126/science.1145697.View ArticlePubMedGoogle Scholar
- Aggarwal S, Kim SW, Cheon K, Tabassam FH, Yoon JH, Koo JS: Nonclassical action of retinoic acid on the activation of the cAMP response element-binding protein in normal human bronchial epithelial cells. Mol Biol Cell. 2006, 17 (2): 566-575.PubMed CentralView ArticlePubMedGoogle Scholar
- Takamura K, Nasuhara Y, Kobayashi M, Betsuyaku T, Tanino Y, Kinoshita I, Yamaguchi E, Matsukura S, Schleimer RP, Nishimura M: Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line. Am J Physiol-lung C. 2004, 286 (4): L777-L785.View ArticleGoogle Scholar
- Denburg JA, Sehmi R, Upham J: Regulation of IL-5 receptor on eosinophil progenitors in allergic inflammation: role of retinoic acid. Int Arch Allergy Immunol. 2001, 124 (1–3): 246-248.View ArticlePubMedGoogle Scholar
- Izuhara K: The role of interleukin-4 and interleukin-13 in the non-immunologic aspects of asthma pathogenesis. Clin Chem Lab Med. 2003, 41 (7): 860-864.View ArticlePubMedGoogle Scholar
- Kumar RK, Herbert C, Yang M, Koskinen AM, McKenzie AN, Foster PS: Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma. Clin Exp Allergy. 2002, 32 (7): 1104-1111. 10.1046/j.1365-2222.2002.01420.x.View ArticlePubMedGoogle Scholar
- Tomasiak-Lozowska MM, Bodzenta-Lukaszyk A, Tomasiak M, Skiepko R, Zietkowski Z: The role of interleukin 13 and interleukin 5 in asthma. Postepy Hig Med Dosw (Online). 2010, 64: 146-155.Google Scholar
- Zhao Y, Yang J, Gao YD, Guo W: Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol. 2009, 151 (4): 297-307.View ArticlePubMedGoogle Scholar
- Wang YH, Wills-Karp M: The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep. 2011, 11 (5): 388-394. 10.1007/s11882-011-0210-y.PubMed CentralView ArticlePubMedGoogle Scholar
- Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, Wang Y, Bernstein X, Li JT, Atabai K, Huang X, Sheppard D: IL-17A produced by alphabeta T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med. 2012, 18 (4): 547-554. 10.1038/nm.2684.PubMed CentralView ArticlePubMedGoogle Scholar
- Barnes PJ: Role of GATA-3 in allergic diseases. Curr Mol Med. 2008, 8 (5): 330-334. 10.2174/156652408785160952.View ArticlePubMedGoogle Scholar
- Kiwamoto T, Ishii Y, Morishima Y, Yoh K, Maeda A, Ishizaki K, Iizuka T, Hegab AE, Matsuno Y, Homma S, Nomura A, Sakamoto T, Takahashi S, Sekizawa K: Transcription factors T-bet and GATA-3 regulate development of airway remodeling. Am J Respir Crit Care Med. 2006, 174 (2): 142-151. 10.1164/rccm.200601-079OC.View ArticlePubMedGoogle Scholar
- Zhao J, Lloyd CM, Noble A: Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol. 2013, 6 (2): 335-346. 10.1038/mi.2012.76.PubMed CentralView ArticlePubMedGoogle Scholar
- McGowan SE, Holmes AJ, Smith J: Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency. Am J Physiol-lung C. 2004, 286 (2): L437-L444. 10.1152/ajplung.00158.2003.View ArticleGoogle Scholar
- Goswami S, Angkasekwinai P, Shan M, Greenlee KJ, Barranco WT, Polikepahad S, Seryshev A, Song LZ, Redding D, Singh B, Sur S, Woodruff P, Dong C, Corry DB, Kheradmand F: Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol. 2009, 10 (5): 496-503. 10.1038/ni.1719.View ArticlePubMedGoogle Scholar
- Maret M, Ruffie C, Periquet B, Campo AM, Menevret M, Phelep A, Dziewiszek K, Druilhe A, Pretolani M: Liposomal retinoic acids modulate asthma manifestations in mice. J nutr. 2007, 137 (12): 2730-2736.PubMedGoogle Scholar
- Bidad K, Salehi E, Jamshidi A, Saboor-Yaraghi AA, Oraei M, Meysamie A, Mahmoudi M, Nicknam MH: Effect of All-transretinoic acid on Th17 and T regulatory cell subsets in patients with ankylosing spondylitis. J Rheumatol. 2013, 40 (4): 476-483. 10.3899/jrheum.121100.View ArticlePubMedGoogle Scholar
- Xia ZW, Xu LQ, Zhong WW, Wei JJ, Li NL, Shao J, Li YZ, Yu SC, Zhang ZL: Heme oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor-1. Am J Pathol. 2007, 171 (6): 1904-1914. 10.2353/ajpath.2007.070096.PubMed CentralView ArticlePubMedGoogle Scholar
- Xia ZW, Zhong WW, Xu LQ, Sun JL, Shen QX, Wang JG, Shao J, Li YZ, Yu SC: Heme oxygenase-1-mediated CD4+CD25high regulatory T cells suppress allergic airway inflammation. J immunol. 2006, 177 (9): 5936-5945.View ArticlePubMedGoogle Scholar
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