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Retinoids Accelerate B Lineage Lymphoid Differentiation¹

Xinrong Chen^*, Brandt L. Esplin^*,, Karla P. Garrett^*, Robert S. Welner^*,, Carol F. Webb^* and Paul W. Kincade^2,*

^* Immunobiology and Cancer Program, Oklahoma Medical Research Foundation and Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

Retinoids are known to have potent effects on hemopoietic stem cell integrity, and our objective was to learn whether they influence cells destined to replenish the immune system. Total CD19⁺ B lineage cells increased substantially in the marrow and spleens of all-trans retinoic acid (ATRA)-treated C57BL6 mice, while lymphoid progenitors were reduced. All B lymphoid progenitors were targets of ATRA in culture and overall cell yields declined without reductions in proliferation. Remarkably, ATRA shortened the time required for primitive progenitors to generate CD19⁺ cells. PCR analysis and a panel of retinoid acid receptor (RAR)/retinoid X receptor agonist treatments suggested that RAR mediates these responses. The transcription factors EBF1 and Pax-5 were elevated during treatment and ATRA had similar effects on human B cell differentiation. That is, it inhibited the expansion of human progenitor cells and accelerated their differentiation to B lineage cells. There may be previously unsuspected side effects of ATRA therapy, and the new findings suggest retinoids can normally contribute to the lymphopoietic environment in bone marrow.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AI20069 and AI58162 from the National Institutes of Health and Grant N01-A1-30070 from the U.S. Immunodeficiency Network. P.W.K. holds the William H. and Rita Bell Endowed Chair in Biomedical Research.

² Address correspondence and reprint requests to Dr. Paul W. Kincade, Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104. E-mail address: kincade{at}omrf.ouhsc.edu

³ Abbreviations used in this paper: ATRA, all-trans retinoic acid; EBF1, early B cell factor 1; ELP, early lymphoid progenitor (Lin^–RAG-1/GFP⁺Sca-1⁺c-Kit^high); FL, Flt3 ligand; HSC, hemopoietic stem cell; LSK, Lin^–Sca-1⁺c-Kit^high; Pax-5, paired box gene 5; PBX1, pre-B cell leukemic homeobox 1; Pro-L, prolymphocyte (Lin^–Sca-1⁺c-Kit^low); RAR, retinoic acid receptor; rh, recombinant human; rm, recombinant murine; RXR, retinoic X receptor; SCF, stem cell factor; sIgM, surface IgM; TSLP, thymic stromal lymphopoietin; TTNPB, 4-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid.

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The JI 2008 180: 1-2. [Full Text]