Anti-inflammatory effects of plumbagin are mediated by inhibition of NF-kappaB activation in lymphocytes

Int Immunopharmacol. 2009 Jul;9(7-8):949-58. doi: 10.1016/j.intimp.2009.03.022. Epub 2009 Apr 15.

Abstract

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.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / immunology
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology
  • Antigens, Differentiation / metabolism
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle / immunology
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Down-Regulation
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / prevention & control
  • I-kappa B Proteins / metabolism
  • Immunosuppression
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lectins, C-Type
  • Lymphocyte Activation / drug effects
  • Male
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Naphthoquinones / pharmacology*
  • Plant Roots
  • Plumbaginaceae*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / immunology

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • Cytokines
  • I kappa B beta protein
  • I-kappa B Proteins
  • Interleukin-2 Receptor alpha Subunit
  • Lectins, C-Type
  • NF-kappa B
  • Naphthoquinones
  • plumbagin