BMC Immunology | |
All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma | |
Zhenwei Xia1  Wenwei Zhong1  Qi Liu1  Yanjie Zhang1  Jinhong Wu1  | |
[1] Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Ruijin 2nd Road 197, Shanghai 200025, China | |
关键词: Regulatory T cells; Th17; Th2; All-trans retinoic acid; Asthma; | |
Others : 1077782 DOI : 10.1186/1471-2172-14-28 |
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received in 2012-12-18, accepted in 2013-06-18, 发布年份 2013 | |
【 摘 要 】
Background
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.
Results
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.
Conclusions
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.
【 授权许可】
2013 Wu et al.; licensee BioMed Central Ltd.
【 预 览 】
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【 参考文献 】
- [1]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.
- [2]Al Senaidy AM: Serum vitamin A and beta-carotene levels in children with asthma. J Asthma 2009, 46(7):699-702.
- [3]McGowan SE: Vitamin A deficiency increases airway resistance following C-fiber stimulation. Respir Physiol Neurobiol 2007, 157(2–3):281-289.
- [4]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.
- [5]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.
- [6]Hall JA, Grainger JR, Spencer SP, Belkaid Y: The role of retinoic acid in tolerance and immunity. Immunity 2011, 35(1):13-22.
- [7]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.
- [8]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.
- [9]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]Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A, et al.: 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 1992, 355(6358):359-361.
- [11]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.
- [12]Pino-Lagos K, Guo Y, Brown C, Alexander MP, Elgueta R, Bennett KA, De Vries V, Nowak E, Blomhoff R, Sockanathan S, et al.: A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J Exp Med 2011, 208(9):1767-1775.
- [13]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.
- [14]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.
- [15]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.
- [16]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.
- [17]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.
- [18]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.
- [19]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.
- [20]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.
- [21]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.
- [22]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.
- [23]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.
- [24]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.
- [25]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.
- [26]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.
- [27]Zhao Y, Yang J, Gao YD, Guo W: Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol 2009, 151(4):297-307.
- [28]Wang YH, Wills-Karp M: The potential role of interleukin-17 in severe asthma. Curr Allergy Asthma Rep 2011, 11(5):388-394.
- [29]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.
- [30]Barnes PJ: Role of GATA-3 in allergic diseases. Curr Mol Med 2008, 8(5):330-334.
- [31]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.
- [32]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.
- [33]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.
- [34]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.
- [35]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.
- [36]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.
- [37]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.
- [38]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.