Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a quinone isolated from the roots of Plumbago zeylanica was recently reported to suppress the activation of NF-kappaB in tumor cells. NF-kappaB, a ubiquitous transcription factor, plays a central role in regulating diverse processes in leukocytes like cellular proliferation, expression of immunoregulatory genes and apoptosis during innate and adaptive immune responses. Consequently, plumbagin might affect the biological functions of leukocytes participating in various immune responses. The present report describes novel immunomodulatory effects of plumbagin. Plumbagin inhibited T cell proliferation in response to polyclonal mitogen Concanavalin A (Con A) by blocking cell cycle progression. It also suppressed expression of early and late activation markers CD69 and CD25 respectively, in activated T cells. At these immunosuppressive doses (up to 5 microM), plumbagin did not reduce the viability of lymphocytes. Further, the inhibition of T cell proliferation by plumbagin was accompanied by a decrease in the levels of Con A induced IL-2, IL-4, IL-6 and IFN-gamma cytokines. Similar immunosuppressive effects of plumbagin on cytokine levels were seen in vivo. To characterize the mechanism of inhibitory action of plumbagin, the mitogen induced IkappaB-alpha degradation and nuclear translocation of NF-kappaB was studied in lymphocytes. Plumbagin completely inhibited Con A induced IkappaB-alpha degradation and NF-kappaB activation. Further, plumbagin prevented Graft Versus Host Disease-induced mortality in mice. To our knowledge this is the first report showing the immunomodulatory effects of plumbagin in lymphocytes via modulation of NF-kappaB activation.
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PMID:Anti-inflammatory effects of plumbagin are mediated by inhibition of NF-kappaB activation in lymphocytes. 1937 55

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.
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PMID:Plumbagin inhibits proliferative and inflammatory responses of T cells independent of ROS generation but by modulating intracellular thiols. 2056 4