The retinoic acid receptor-α modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression

Clinical and Molecular Allergy

Calman Prussin¹  Yuzhi Yin¹  Daniel L Wansley¹ 

[1] National Institute of Allergy and Infectious Disease, National Institutes of Health, Laboratory of Allergic Diseases, NIH, 10 Center Drive, MSC-1881, Bethesda, MD, 20852-1881, USA

关键词: Retinoic acid response element;    House dust mite antigen;    Retinoic acid receptor alpha;    T helper 2;    All-trans retinoic acid;    Interleukin 5;   

Others  :  790480
DOI  :  10.1186/1476-7961-11-4

 received in 2013-08-27, accepted in 2013-11-23,  发布年份 2013

【 摘 要 】

Background

Th2 cytokine responses are enhanced by all trans retinoic acid (ATRA), the bioavailable form of vitamin A. Retinoic acid receptor alpha (RARα) is the high affinity receptor for ATRA that mediates these pro-Th2 effects. We have previously characterized two major human Th2 subpopulations: IL-5- Th2 (IL-5-, IL-4+, IL-13+) and IL-5+ Th2 cells (IL-5+, IL-4+, IL-13+), which represent less and more highly differentiated Th2 cells, respectively. We hypothesized that the pro-Th2 effects of ATRA may differentially affect these Th2 subpopulations.

Methods

Specific cytokine producing Th2 subpopulations were identified using intracellular cytokine staining. Proliferation was measured using the Cell Trace Violet proliferation tracking dye. Apoptotic cells were identified using either annexin-V or active caspase 3 staining. Th2 gene expression was measured using quantitative polymerase chain reaction.

Results

ATRA increased the output of Th2 cells from house dust mite allergen (HDM) specific short-term cell lines, and this enhancement was limited to the IL-5+ Th2 subpopulation. Conversely, the RARα antagonist Ro415253 decreased Th2 cell output from these cultures, and this effect was again limited to the IL-5+ Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited Th2 cell proliferation, and this affect was more pronounced for the IL-5+ vs. IL-5- Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited the expression of IL5 in a significant manner, which was not found for IL4 or IL13.

Conclusions

We report that the reciprocal regulation of Th2 cytokine expression and proliferation by RARα modulators are largely limited to modulation of IL-5 gene expression and to proliferation of the highly differentiated IL-5+ Th2 subpopulation. These results suggest that RARα antagonism is a potential means to therapeutically target allergic inflammation.

Trial registration

Clinicaltrials.gov identifier: NCT01212016

【 授权许可】

   
2013 Wansley et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Green HN, Mellanby E: Vitamin a as an anti-infective agent. Br Med J 1928, 2:691-696.
• [2]Mellanby E, Green HN: Vitamin a as an anti-infective agent: its Use in the treatment of puerperal septigaemia. Br Med J 1929, 1:984-986.
• [3]Veldhoen M, Brucklacher-Waldert V: Dietary influences on intestinal immunity. Nat Rev Immunol 2012, 12:696-708.
• [4]Hall JA, Grainger JR, Spencer SP, Belkaid Y: The role of retinoic acid in tolerance and immunity. Immunity 2011, 35:13-22.
• [5]Hall JA, Cannons JL, Grainger JR, Dos Santos LM, Hand TW, Naik S, Wohlfert EA, Chou DB, Oldenhove G, Robinson M, et al.: Essential role for retinoic acid in the promotion of CD4(+) T cell effector responses via retinoic acid receptor alpha. Immunity 2011, 34:435-447.
• [6]Dawson HD, Collins G, Pyle R, Key M, Taub DD: The retinoic acid receptor-alpha mediates human T-cell activation and Th2 cytokine and chemokine production. BMC Immunol 2008, 9:16. BioMed Central Full Text
• [7]Ohoka Y, Yokota A, Takeuchi H, Maeda N, Iwata M: Retinoic acid-induced CCR9 expression requires transient TCR stimulation and cooperativity between NFATc2 and the retinoic acid receptor/retinoid X receptor complex. J Immunol 2011, 186:733-744.
• [8]Vaishnava S, Hooper LV: Eat your carrots! T cells are RARing to go. Immunity 2011, 34:290-292.
• [9]Pino-Lagos K, Guo Y, Noelle RJ: Retinoic acid: a key player in immunity. Biofactors 2010, 36:430-436.
• [10]Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL: Two types of murine helper T cell clone. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986, 136:2348-2357.
• [11]Carman JA, Pond L, Nashold F, Wassom DL, Hayes CE: Immunity to Trichinella spiralis infection in vitamin A-deficient mice. J Exp Med 1992, 175:111-120.
• [12]Lei GS, Zhang C, Shao S, Jung HW, Durant PJ, Lee CH: All-trans retinoic acid in combination with primaquine clears pneumocystis infection. PLoS One 2013, 8:e53479.
• [13]Broadhurst MJ, Leung JM, Lim KC, Girgis NM, Gundra UM, Fallon PG, Premenko-Lanier M, McKerrow JH, McCune JM, Loke P: Upregulation of retinal dehydrogenase 2 in alternatively activated macrophages during retinoid-dependent type-2 immunity to helminth infection in mice. PLoS Pathog 2012, 8:e1002883.
• [14]Cantorna MT, Nashold FE, Hayes CE: In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J Immunol 1994, 152:1515-1522.
• [15]Schuster GU, Kenyon NJ, Stephensen CB: Vitamin A deficiency decreases and high dietary vitamin A increases disease severity in the mouse model of asthma. J Immunol 2008, 180:1834-1842.
• [16]Dawson HD, Collins G, Pyle R, Key M, Weeraratna A, Deep-Dixit V, Nadal CN, Taub DD: Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. BMC Immunol 2006, 7:27. BioMed Central Full Text
• [17]Upadhyaya B, Yin Y, Hill BJ, Douek DC, Prussin C: Hierarchical IL-5 expression defines a subpopulation of highly differentiated human Th2 cells. J Immunol 2011, 187:3111-3120.
• [18]Islam SA, Chang DS, Colvin RA, Byrne MH, McCully ML, Moser B, Lira SA, Charo IF, Luster AD: Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ T(H)2 cells. Nat Immunol 2011, 12:167-177.
• [19]Endo Y, Iwamura C, Kuwahara M, Suzuki A, Sugaya K, Tumes DJ, Tokoyoda K, Hosokawa H, Yamashita M, Nakayama T: Eomesodermin controls interleukin-5 production in memory T helper 2 cells through inhibition of activity of the transcription factor GATA3. Immunity 2011, 35:733-745.
• [20]Prussin C, Lee J, Foster B: Eosinophilic gastrointestinal disease and peanut allergy are alternatively associated with IL-5+ and IL-5(-) T(H)2 responses. J Allergy Clin Immunol 2009, 124(1326–1332):e1326.
• [21]Givan AL, Fisher JL, Waugh M, Ernstoff MS, Wallace PK: A flow cytometric method to estimate the precursor frequencies of cells proliferating in response to specific antigens. J Immunol Methods 1999, 230:99-112.
• [22]Givan AL, Fisher JL, Waugh MG, Bercovici N, Wallace PK: Use of cell-tracking dyes to determine proliferation precursor frequencies of antigen-specific T cells. Methods Mol Biol 2004, 263:109-124.
• [23]Blalock EM: A Beginner’s Guide to Microarrays. Norwell: Kluwer Academic Publishers; 2003.
• [24]Cui D, Moldoveanu Z, Stephensen CB: High-level dietary vitamin a enhances T-helper type 2 cytokine production and secretory immunoglobulin a response to influenza a virus infection in BALB/c mice. J Nutr 2000, 130:1132-1139.
• [25]Greasley PJ, Clapham JC: Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing? Eur J Pharmacol 2006, 553:1-9.
• [26]Ruiter B, Shreffler WG: Innate immunostimulatory properties of allergens and their relevance to food allergy. Semin Immunopathol 2012, 34:617-632.
• [27]Schupp M, Curtin JC, Kim RJ, Billin AN, Lazar MA: A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity. Mol Pharmacol 2007, 71:1251-1257.