title: IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2.
abstract: Although activated inflammatory monocytes (IMCs) and inflammatory dendritic cells (IDCs) are potent T cell suppressors, nonactivated IMCs and IDCs promote T cell activation and Th1/Th17 cell differentiation. In this study, we investigated how to reduce the proinflammatory properties of IMCs and IDCs and further convert them into immune regulatory dendritic cells (DCs). We found that IL-4 and retinoic acid (RA) cotreatment of GM-CSF-differentiated IDCs synergistically induced the expression of aldehyde dehydrogenase family 1, subfamily A2, a rate-limiting enzyme for RA synthesis in DCs. IL-4 plus RA-treated IDCs upregulated CD103 expression and markedly reduced the production of proinflammatory cytokines upon activation. IL-4 plus RA-treated IDCs strongly induced CD4⁺Foxp3⁺ regulatory T cell differentiation and suppressed Th1 and Th17 differentiation. Mechanistically, the transcription factors Stat6 and RA receptor β play important roles in aldehyde dehydrogenase family 1, subfamily A2, induction. In addition, IL-4 and RA signaling pathways interact closely to enhance the regulatory function of treated DCs. Adoptive transfer of IL-4 plus RA-treated DCs significantly increased regulatory T cell frequency in vivo. Direct treatment with IL-4 and RA also markedly suppressed actively induced experimental autoimmune encephalomyelitis. Our data demonstrate the synergistic effect of IL-4 and RA in inducing a regulatory phenotype in IDCs, providing a potential treatment strategy for autoimmune diseases.
authors: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. bing6335@yahoo.com
authors: Bing
authors: B
authors: Zhu
authors: Thomas
authors: T
authors: Buttrick
authors: Ribal
authors: R
authors: Bassil
authors: Chen
authors: C
authors: Zhu
authors: Marta
authors: M
authors: Olah
authors: Chuan
authors: C
authors: Wu
authors: Sheng
authors: S
authors: Xiao
authors: William
authors: W
authors: Orent
authors: Wassim
authors: W
authors: Elyaman
authors: Samia J
authors: SJ
authors: Khoury
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000276:immunology; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D050697:Retinal Dehydrogenase; D014212:Tretinoin / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015847:Interleukin-4; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase
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