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Pathway Development Via Retinoid X Receptor Vitamin a Enhances In Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway This information is current as Charles B. Stephensen, Reuven Rasooly, Xiaowen Jiang, of September 24, 2021. Michael A. Ceddia, Casey T. Weaver, Roshantha A. S. Chandraratna and R. Patterson Bucy J Immunol 2002; 168:4495-4503; ; doi: 10.4049/jimmunol.168.9.4495 http://www.jimmunol.org/content/168/9/4495 Downloaded from References This article cites 40 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/168/9/4495.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway1 Charles B. Stephensen,2* Reuven Rasooly,* Xiaowen Jiang,* Michael A. Ceddia,3* Casey T. Weaver,† Roshantha A. S. Chandraratna,‡ and R. Patterson Bucy† Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses. To identify a potential mechanism(s) underlying this in vivo activity of vitamin A, we examined the effects of all-trans and 9-cis RA on development of Th1 and Th2 cell populations using in vitro stimulation of Ag-naive Th0 cells from the DO11.10 TCR-transgenic mouse. Treatment with 9-cis, but not with all-trans RA, at primary stimulation strongly enhanced Th2 development. IL-4-neutralizing Ab blocked this activity, but IL-12- and IFN-␥- neutralizing Ab did not. Because 9-cis RA regulates gene transcription via either RA receptors or retinoid X receptors (RXRs), we tested the Th2-enhancing activities of the RXR- and RA receptor-selective agonists AGN194204 and 4-((E)-2-(5,6,7,8-tetra- Downloaded from hydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB). AGN194204 strongly enhanced Th2 development, (whereas TTNPB did not. This RXR agonist also enhanced Th2 development when purified, naive Th0 cells (L-selectinhigh/CD4؉ were stimulated with CD3 and CD28 Abs in the absence of APCs. During primary antigenic stimulation of naive Th0 cells from DO11.10 mice, AGN194204 increased IL-4 and IL-5 production, decreased IFN-␥ production, increased mRNA in responding T cells for genes involved in Th2 development (IL-4, GATA-3, and c-maf), and decreased mRNA for genes involved in Th1 devel- opment (IFN-␥, T-bet, and IL-12R). These data show that stimulation of the RXR pathway enhances Th2 development, perhaps http://www.jimmunol.org/ by affecting the relative expression of pertinent transcription factors, cytokines, and cytokine receptors. The Journal of Immu- nology, 2002, 168: 4495–4503. itamin A deficiency increases mortality from common increases IL-5, IL-10, and IL-4 production (11–13). Thus, vitamin childhood infections (1, 2). The specific mechanisms un- A deficiency biases the immune response in a Th1 direction, V derlying this increased risk of death have not been whereas high-level dietary vitamins may bias the response in a Th2 clearly defined but presumably involve impairment of specific and direction. RA appears to be the metabolite of vitamin A that is nonspecific host defense mechanisms (3). Although data from hu- most potent in restoring impaired Ab responses (14). Although it by guest on September 24, 2021 mans are limited, rodent studies indicate that vitamin A deficiency is known that exogenous RA can down-regulate IFN-␥ transcrip- alters the Ab response to T cell-dependent Ags (4, 5). Vitamin A tion (15), little else is known about how RA modulates Th1/Th2 deficiency decreases the IgA, IgG1, and IgE responses but in- balance. creases the IgG2a response to viral infection (6–8). The underly- Vitamin A and other fat-soluble nutrients are precursors for ing pattern of cytokine production by APCs and T cells is consis- compounds that act as ligands for nuclear receptors that regulate tent with these effects on Ab production: vitamin A deficiency gene transcription in response to changes in nutritional status (16). increases constitutive IL-12 production by macrophages (9), and These receptors regulate key metabolic processes, such as energy during secondary in vitro stimulation of lymphocytes with Ag, metabolism, but are also found in cells of the immune system vitamin A deficiency increases IFN-␥ production, but decreases where they appear to modulate immune function based on envi- IL-4 and IL-5 production (10). Conversely, supplemental treat- ronmental (in this case, nutritional) signals. The vitamin A deriv- ment with vitamin A or retinoic acid (RA)4 decreases IFN-␥ and atives all-trans and 9-cis RA regulate gene transcription by bind- ing to the RA receptors (RARs) ␣, ␤,or␥ or to the retinoid X receptors (RXRs) ␣, ␤,or␥ (17, 18). Both all-trans and 9-cis RA *U.S. Department of Agriculture Western Human Nutrition Research Center and Nutrition Department, University of California, Davis, CA 95616; †Department of bind to the RARs, whereas 9-cis RA also acts via the RXRs. Do- Pathology, School of Medicine, University of Alabama, Birmingham, AL 35243; and cosahexaenoic acid also binds to RXRs and may be a physiolog- ‡Departments of Chemistry and Biology, Retinoid Research, Allergan, Irvine, CA 92623 ically important ligand in tissues in which concentrations are suf- ficient (Ն10 ␮mol/L) to trigger transcriptional regulation (19). Received for publication December 18, 2001. Accepted for publication March 1, 2002. RAR and RXR belong to a family of nuclear receptors that also The costs of publication of this article were defrayed in part by the payment of page includes the vitamin D receptor (VDR), thyroid hormone receptor, charges. This article must therefore be hereby marked advertisement in accordance and the peroxisome proliferation/activation receptor (PPAR), with 18 U.S.C. Section 1734 solely to indicate this fact. which binds specific fatty acids. In brief, the structure of these 1 This work was supported by the U.S. Department of Agriculture, National Research receptors includes a 5Ј “A/B” domain, a DNA-binding “C” do- Initiative Grant No. 97-35200-4229, and program funds from the Western Human Nutrition Research Center. main, a hinge region (“D” domain), the ligand-binding “E” do- Ј 2 Address correspondence and reprint requests to Dr. Charles B. Stephensen, Nutri- main, and a 3 “F” domain of uncertain function. Receptors bind to tion Department, University of California, 3243 Meyer Hall, One Shields Avenue, specific DNA response elements in the regulatory regions of genes Davis, CA 95616. E-mail address: [email protected] 3 Current address: IAMS, 6571 State Route 503 North, Lewisburg, OH 45338. 4 Abbreviations used in this paper: RA, retinoic acid; RAR, RA receptor; RXR, ret- tion receptor; TTNPB, 4-((E)-2-(5,6, 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthale- inoid X receptor; VDR, vitamin D receptor; PPAR, peroxisome proliferation/activa- nyl)-1-propenyl)benzoic acid. Copyright © 2002 by The American Association of Immunologists 0022-1767/02/$02.00 4496 RXR AGONISTS ENHANCE IN VITRO Th2 DEVELOPMENT for which transcription is regulated by these receptors. Transcrip- gies; containing penicillin, streptomycin, and fungizone), 5 ml nonessential tional activity is regulated via specific receptor sequences that in- amino acid mix (Life Technologies), 5 ml sodium pyruvate (Life Technol- teract with coactivator proteins to affect transcription by RNA ogies), and 0.25 ml of 100 mM 2-ME (Life Technologies). Cells were centrifuged at 800 ϫ g at 4°C for 10 min. Contaminating RBCs were then polymerase II. Sequences in the ligand binding domain are also lysed by adding red cell lysis buffer. Cells were again centrifuged and responsible for formation of heterodimers among these receptors, resuspended in Russ-10 medium, and viable cells were counted using with RXR being one of the heterodimer partners. Unlike other trypan blue and a hemocytometer. Serum-free medium, made as described receptors, RXR can also form homodimers that can positively reg- above with 1% HL-1 serum replacement (BioWhittaker, Walkersville, MD) instead of 10% serum, was used in some experiments. In some ex- ulate transcription. In these experiments, we used all-trans RA periments, CD4ϩ cells were positively selected using Ab-coated magnetic (which binds to RAR), 9-cis RA (which binds to both RAR and beads (CD4 Dynabead; Dynal Biotech, Oslo, Norway) and a magnetic RXR), the RAR-selective retinoid 4-((E)-2-(5,6,7,8-tetrahydro- particle concentrator (MPC-2; Dynal Biotech). CD4ϩ cells were then de- tached from the magnetic beads using an Ab reagent (mouse CD4 Detach- 5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TT- ϩ NPB), and the RXR-selective retinoid AGN194204 (20, 21) to a-bead; Dynal Biotech). Positively selected CD4 cells, unselected lymph node cells, and a remixture of the selected and unselected cells were com- demonstrate that stimulation of the RXR pathway enhances Th2 pared for their ability to produce IL-4 and IFN-␥ after antigenic stimulation development. Use of these latter compounds is particularly impor- (as described in Stimulation protocol) under Th2 conditions (1000 U/ml, 10 tant because they are stable, whereas RA isomers can interconvert ng/ml IL-4; BD PharMingen), nonselective conditions (no additional cy- tokine or Ab), and Th1 conditions (5 ␮g/ml anti-IL-4 plus 10 U/ml, 0.2 under physiologic conditions (18).
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