title: Inosine monophosphate dehydrogenase (IMPDH) inhibition in vitro suppresses lymphocyte proliferation and the production of immunoglobulins, autoantibodies and cytokines in splenocytes from MRLlpr/lpr mice.
abstract: The aim of this study was to evaluate the effects of the immunomodulating drug mycophenolic acid (MPA) on splenocytes in an animal model of systemic lupus erythematosus (SLE), using MRLlpr/lpr mice. MPA reversibly inhibits inosine 5'-monophosphate dehydrogenase, an enzyme involved in the de novo guanosine synthesis. Splenocytes were treated with MPA (at 1 or 10 microM), and stimulated with either lipopolysaccharide (LPS; 10 microg/ml) or concanavalin A (ConA; 1.25 microg/ml). In blocking experiments, guanosine (100 microM) was added to the cultures to inhibit the effects of MPA. Lymphocyte proliferation, enumeration of immunoglobulin producing cells (using ELISPOT) and quantification of anti-double-stranded (ds) DNA antibodies, IFN-gamma and IL-10 (by ELISA) in supernatants were performed. In addition, cell viability was evaluated using propidium iodide and flow cytometry. We found that MPA-treated splenocytes had dramatically decreased mitogen-induced proliferation and number of immunoglobulin producing cells, down-regulated production of IFN-gamma, IL-10 and IgM anti-dsDNA antibodies. The viability of MPA-treated cells was also decreased. All of the effect modulated by MPA could be neutralized by the addition of guanosine. We conclude that MPA has potent immunomodulating effects on both B and T lymphocytes, modulating not only proliferation, but also the production of cytokines, immunoglobulins and autoantibodies.
authors.affiliation: Department of Rheumatology, Göteborg University, Sweden. charlotte.jonsson@rheuma.gu.se
authors.forename: C A
authors.initials: CA
authors.lastname: Jonsson
authors.forename: H
authors.initials: H
authors.lastname: Carlsten
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006151:Guanosine / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007075:Immunoglobulin M / Q000378:metabolism; D007136:Immunoglobulins / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008934:Mitogens / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000494:pharmacology; D013154:Spleen / Q000166:cytology
chemical_list: D000276:Adjuvants, Immunologic; D000974:Antibodies, Antinuclear; D004791:Enzyme Inhibitors; D007075:Immunoglobulin M; D007136:Immunoglobulins; D008070:Lipopolysaccharides; D008934:Mitogens; D003208:Concanavalin A; D006151:Guanosine; D016753:Interleukin-10; D007371:Interferon-gamma; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid