title: Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen-induced arthritis.
abstract: Prodigiosin (PDG) was previously reported to be a T cell-specific immunosuppressant. Here we describe the mechanism of action of PDG in T cells and the effect of PDG on autoimmune diseases. PDG selectively suppresses concanavalin A (Con A)-induced T cell proliferation, but has little effect on lipopolysaccharide-induced proliferation of B cells and nitric oxide production of macrophages. Although PDG does not block interleukin (IL)-2 production, it efficiently inhibits interleukin-2 receptor alpha-chain (IL-2Ralpha) expression, and this results in a disruption of the IL-2/IL-2R signaling pathway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting interferon-gamma and IL-4 as well as into effector cytotoxic T lymphocytes expressing perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activator of transcription activation by inhibiting cytokine signalings in Con A-activated T cells, although it does not inhibit the activation of nuclear factor-kappaB, nuclear factor of activated T cells, and activator protein-1. As direct evidence of immunosuppression in vivo, we show that PDG markedly reduced blood glucose levels and cellular infiltration into the pancreatic islets in nonobese diabetic mice, and that it also delays the onset of collagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstrate that PDG has a unique mode of action, namely, that it blocks T cell activation by inhibiting primarily IL-2Ralpha expression in the IL-2/IL-2R signaling, and show that this compound represents a promising immunosuppressant candidate for the treatment of autoimmune diseases.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yusong, Taejon, Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Han
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.forename: Y J
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Y K
authors.initials: YK
authors.lastname: Kim
authors.forename: H M
authors.initials: HM
authors.lastname: Kim
authors.forename: K H
authors.initials: KH
authors.lastname: Yang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology; D001168:Arthritis / Q000139:chemically induced / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D003094:Collagen; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009573:Nitrites / Q000378:metabolism; D011353:Prodigiosin / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D018501:Antirheumatic Agents; D016207:Cytokines; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D009573:Nitrites; D018123:Receptors, Interleukin; D016572:Cyclosporine; D003094:Collagen; D011353:Prodigiosin