title: Roles of reactive nitrogen intermediates and transforming growth factor-beta produced by immunosuppressive macrophages in the expression of suppressor activity against T cell proliferation induced by TCR stimulation.
abstract: The suppressor activity of splenic macrophages induced by Mycobacterium intracellulare infection (MI-M phi s) against T cell concanavalin A (Con A) mitogenesis is mediated by MI-M phi's mediators, such as reactive nitrogen intermediates (RNIs), phosphatidylserine, free fatty acids, prostaglandin E(2) and to a minor extent TGF-beta. Here, we have compared the roles of RNIs and TGF-beta in the expression of MI-M phi's suppressor activity against Con A mitogenesis and anti-CD3 monoclonal antibody (mAb)- and anti-CD28 mAb-induced mitogenesis (TCR signal-induced mitogenesis) of the target T cells, and have found the following. First, N(G)-monomethyl-L-arginine (NMMA) inhibited MI-M phi's suppressor activity against TCR signal-induced mitogenesis as well as Con A mitogenesis. Second, anti-TGF-beta mAb weakly restored the MI-M phi-mediated suppression only in the case of Con A mitogenesis, under limited conditions, such as very low cell densities of MI-M phi s. Third, the blocking effects of NMMA plus anti-TGF-beta mAb were somewhat more prominent in the case of Con A mitogenesis than in the case of TCR signal-induced mitogenesis. Fourth, Con A- or TCR signal-stimulated MI-M phi s secreted significant amounts of the latent TGF-beta but not the active one. These findings indicate that RNIs, but not TGF-beta, play important roles in the MI-M phi-mediated suppression of TCR signal-induced mitogenesis, as well as Con A mitogenesis, of the target T cells.
authors.affiliation: Department of Microbiology and Immunology, Shimane University School of Medicine, Izumo, Shimane 693-8501, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Shanshan
authors.initials: S
authors.lastname: Cai
authors.forename: Haruaki
authors.initials: H
authors.lastname: Tomioka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D017951:Antigen Presentation; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis / Q000737:chemistry; D003208:Concanavalin A / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015269:Mycobacterium avium Complex / Q000378:metabolism; D015270:Mycobacterium avium-intracellulare Infection / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D026361:Reactive Nitrogen Species; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D026361:Reactive Nitrogen Species; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D003208:Concanavalin A; D019323:omega-N-Methylarginine; D009584:Nitrogen