title: Plumbagin inhibits proliferative and inflammatory responses of T cells independent of ROS generation but by modulating intracellular thiols.
abstract: Plumbagin inhibited activation, proliferation, cytokine production, and graft-versus-host disease in lymphocytes and inhibited growth of tumor cells by suppressing nuclear factor-kappaB (NF-kappaB). Plumbagin was also shown to induce reactive oxygen species (ROS) generation in tumor cells via an unknown mechanism. Present report describes a novel role of cellular redox in modulation of immune responses in normal lymphocytes by plumbagin. Plumbagin depleted glutathione (GSH) levels that led to increase in ROS generation. The decrease in GSH levels was due to direct reaction of plumbagin with GSH as evinced by mass spectrometric and HPLC analysis. Further, addition of plumbagin to cells resulted in decrease in free thiol groups on proteins and increase in glutathionylation of proteins. The suppression of mitogen-induced T-cell proliferation and cytokine (IL-2/IL-4/IL-6/IFN-gamma) production by plumbagin was abrogated by thiol antioxidants but not by non-thiol antioxidants confirming that thiols but not ROS play an important role in biological activity of plumbagin. Plumbagin also abrogated mitogen-induced phosphorylation of ERK, IKK, and degradation of IkappaB-alpha. However, it did not affect phosphorylation of P38, JNK, and AKT. Our results for the first time show that antiproliferative effects of plumbagin are mediated by modulation of cellular redox. These results provide a rationale for application of thiol-depleting agents as anti-inflammatory drugs.
authors.affiliation: Radiation Biology & Health Sciences Division, Bio-Medical Group, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Checker
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sandur
authors.forename: G
authors.initials: G
authors.lastname: Subrahmanyam
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.forename: T B
authors.initials: TB
authors.lastname: Poduval
authors.forename: K B
authors.initials: KB
authors.lastname: Sainis
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D018836:Inflammation Mediators; D007376:Interleukin-2; D015850:Interleukin-6; D008934:Mitogens; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D003208:Concanavalin A; D015847:Interleukin-4; D007371:Interferon-gamma; D002374:Catalase; D013482:Superoxide Dismutase; D005978:Glutathione; C014758:plumbagin