title: Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells.
abstract: While most studies have suggested multipotential stromal cell or mesenchymal stem cell (MSC) therapies are useful for immune-mediated diseases, MSCs' immunomodulatory effects were not entirely reproduced in some studies, indicating the necessity to determine the underlying mechanism of MSCs' effects on immune response regulation to maximize their immunomodulatory effects. We have identified the transcription factor early growth response gene-2 (EGR2) as a novel molecular switch regulating known immunomodulatory molecules in human MSCs. EGR2 binds to the promoter regions of these genes, interleukin-6 (IL6), leukemia inhibitory factor (LIF), indoleamine dioxygenase-1 (IDO1), and cyclooxygenase-2/prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), and siRNA against EGR2 was shown to downregulate these genes and reduce the production of prostaglandin E2, an immunomodulatory mediator produced downstream of COX2/PTGS2. Moreover, EGR2 knockdown restores T-lymphocyte proliferation reduced by MSC coculture. Therefore, EGR2 is a potential target for the optimization of immunomodulatory properties of MSC-based therapies.
authors.affiliation: 1 Department of Pathology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Dominique J
authors.initials: DJ
authors.lastname: Barbeau
authors.forename: Kiet Tran
authors.initials: KT
authors.lastname: La
authors.forename: Duk Soo
authors.initials: DS
authors.lastname: Kim
authors.forename: Svetoslava S
authors.initials: SS
authors.lastname: Kerpedjieva
authors.forename: Galina V
authors.initials: GV
authors.lastname: Shurin
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tamama
mesh_terms: D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis; D015536:Down-Regulation; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D056747:Immunomodulation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; C576710:IDO1 protein, human; C508600:IL6 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone