GA (gambogic acid) is a polyprenylated xanthone abundant in the resin of Garcinia morella and Garcinia hanburyi with a long history of use as a complementary and alternative medicine. The antitumour activity of GA has been well demonstrated and is thought to arise partly from the associated anti-inflammatory activity. Recent studies have indicated that the antitumour activity of GA is mediated by its ligation of TfR1 (transferrin receptor-1). Since the cellular expression of TfR1 is down-regulated by LPS (lipopolysaccharide), we hypothesized that an alternative pathway exists in immune cells, such as macrophages, where GA could mitigate the expression of pro-inflammatory genes. Here we demonstrate that GA inhibits the LPS-dependent expression of NF-κB (nuclear factor κB) target pro-inflammatory genes in macrophages. Western immunoblot, NF-κB-luciferase reporter and gel-shift analyses revealed that GA strongly blocked the activation of NF-κB induced by LPS, whereas 9,10-dihydro-GA, which lacks the reactive α,β-unsaturated carbonyl group, was ineffective. Moreover, GA was able to decrease nuclear p65 levels in RAW264.7 macrophages, where the expression of TfR1 was down-regulated by RNA interference. in vitro kinase assays coupled with interaction studies using biotinylated GA as well as proteomic analysis demonstrated that IKKβ [IκB (inhibitory κB) kinase-β], a key kinase of the NF-κB signalling axis, was covalently modified by GA at Cys-179, causing significant inhibition of its kinase activity. Taken together, these results demonstrate the potent anti-inflammatory activity of GA.
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Research Article|
March 27 2009
Gambogic acid covalently modifies IκB kinase-β subunit to mediate suppression of lipopolysaccharide-induced activation of NF-κB in macrophages Available to Purchase
Umamaheshwari D. Palempalli;
Umamaheshwari D. Palempalli
1
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Ujjawal Gandhi;
Ujjawal Gandhi
1
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Parisa Kalantari;
Parisa Kalantari
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Hema Vunta;
Hema Vunta
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Ryan J. Arner;
Ryan J. Arner
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Vivek Narayan;
Vivek Narayan
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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Anand Ravindran;
Anand Ravindran
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
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K. Sandeep Prabhu
K. Sandeep Prabhu
2
1Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, 115 Henning Building, The Pennsylvania State University, University Park, PA 16802, U.S.A.
2To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
August 05 2008
Revision Received:
January 06 2009
Accepted:
January 14 2009
Accepted Manuscript online:
January 14 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 419 (2): 401–409.
Article history
Received:
August 05 2008
Revision Received:
January 06 2009
Accepted:
January 14 2009
Accepted Manuscript online:
January 14 2009
Citation
Umamaheshwari D. Palempalli, Ujjawal Gandhi, Parisa Kalantari, Hema Vunta, Ryan J. Arner, Vivek Narayan, Anand Ravindran, K. Sandeep Prabhu; Gambogic acid covalently modifies IκB kinase-β subunit to mediate suppression of lipopolysaccharide-induced activation of NF-κB in macrophages. Biochem J 15 April 2009; 419 (2): 401–409. doi: https://doi.org/10.1042/BJ20081482
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