title: GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity.
abstract: Retinoic acid (RA) produced by intestinal dendritic cells (DCs) imprints gut-homing specificity on lymphocytes and enhances Foxp3(+) regulatory T-cell differentiation. The expression of aldehyde dehydrogenase (ALDH) 1A in these DCs is essential for the RA production. However, it remains unclear how the steady-state ALDH1A expression is induced under specific pathogen-free (SPF) conditions. Here, we found that bone marrow-derived dendritic cells (BM-DCs) generated with granulocyte-macrophage colony-stimulating factor (GM-CSF) expressed Aldh1a2, an isoform of Aldh1a, but that fms-related tyrosine kinase 3 ligand-generated BM-DCs did not. DCs from mesenteric lymph nodes (MLN) and Peyer's patches (PP) of normal SPF mice expressed ALDH1A2, but not the other known RA-producing enzymes. Employing a flow cytometric method, we detected ALDH activities in 10-30% of PP-DCs and MLN-DCs. They were CD11c(high)CD4(-/low)CD8alpha(intermediate)CD11b(-/low) F4/80(low/intermediate)CD45RB(low)CD86(high)MHC class II(high)B220(-)CD103(+). Equivalent levels of aldehyde dehydrogenase activity (ALDHact) and ALDH1A2 expression were induced synergistically by GM-CSF and IL-4 in splenic DCs in vitro. In BM-DCs, however, additional signals via Toll-like receptors or RA receptors were required for inducing the equivalent levels. The generated ALDH1A2(+) DCs triggered T cells to express gut-homing receptors or Foxp3. GM-CSF receptor-deficient or vitamin A-deficient mice exhibited marked reductions in the ALDHact in intestinal DCs and the T cell number in the intestinal lamina propria, whereas IL-4 receptor-mediated signals were dispensable. GM-CSF(+)CD11c(-)F4/80(+) cells existed constitutively in the intestinal tissues. The results suggest that GM-CSF and RA itself are pivotal among multiple microenvironment factors that enable intestinal DCs to produce RA.
authors.affiliation: Laboratory of Biodefense Research, Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki-shi, Kagawa, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yokota
authors.forename: Hajime
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Naoko
authors.initials: N
authors.lastname: Maeda
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Ohoka
authors.forename: Chieko
authors.initials: C
authors.lastname: Kato
authors.forename: Si-Young
authors.initials: SY
authors.lastname: Song
authors.forename: Makoto
authors.initials: M
authors.lastname: Iwata
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007422:Intestines / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D051941:fms-Like Tyrosine Kinase 3 / Q000494:pharmacology
chemical_list: D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase; D051941:fms-Like Tyrosine Kinase 3