International Journal of Immunopharmacology
Curcuma longa inhibits TNF-α induced expression of adhesion molecules on human umbilical vein endothelial cells☆
Introduction
Extracts prepared from Curcuma longa have been used for centuries for the treatment of various inflammatory and other diseases [1]. C. longa has been shown to have anti-inflammatory activity as tested in carrageenan induced paw edema and Freund’s adjuvant induced arthritis model [2], [3]. The induction of various cell adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on the endothelial cells is directly involved in inflammation (reviewed by Springer [4]). These cell adhesion proteins are not normally present on the endothelial cell surface but are induced by various pro-inflammatory cytokines such as IL-1 and TNF-α [5], [6].
As the upregulation of these proteins on endothelial cells has been shown to be associated with various inflammatory diseases (reviewed by Gorski [7]), various strategies have been tried to down-regulate the expression of these molecules [8]. Also it has been shown that ICAM-1 deficient mice are protected against ischemic renal injury [9]. Various small molecules, such as glucocorticoids, aspirin, pentoxifylline, etc. have also been shown to block the expression of cell adhesion molecules and have been found to be effective in controlling various inflammatory diseases [10], [11], [12].
Since C. longa has anti-inflammatory activity and expression of adhesion molecules plays an important role in inflammation, we sought to identify and characterise the active principles in the ethyl acetate extract of ground-dried rhizome of C. longa. We report here that diferuloylmethane is the most active component present in the ethyl acetate extract of C. longa for inhibiting TNF-α induced ICAM-1, VCAM-1 and E-selectin expression on the human umbilical vein endothelial cells (HUVECs). We also report that the inhibition by diferuloylmethane is time dependent and is reversible, and it probably interferes with the induction of transcription by TNF-α.
Section snippets
Materials
The human umbilical vein endothelial cell line CRL 1730 was obtained from American Type Culture Collection (Rockville, MD). TNF-α, anti-ICAM-1 (BBA3), anti-VCAM-1 (BBA6) and anti-E-selectin (BBA1) antibodies were purchased from R and D Systems, California. M199, l-glutamine, penicillin, streptomycin, amphotericin, endothelial cell growth factor, trypsin, Pucks saline, HEPES, o-phenylenediamine dihydrochloride, anti-mouse IgG-HRP, anti-mouse IgG-FITC were purchased from Sigma Chemical Co., USA.
Ethyl acetate extract of C. longa inhibits TNF-α induced ICAM-1 expression on endothelial cells in a dose dependent manner
To examine the effect of ethyl acetate extract of C. longa, HUVECs were incubated without or with the extract at various dilutions for 1 h prior to induction with TNF-α (10 ηg/ml) for 16 h. The time of incubation and concentration of the extracts used in these experiments had no effect on the viability as determined by trypan blue staining and morphology of the endothelial cells (data not shown). As detected by ELISA, ICAM-1 was expressed at low levels on unstimulated endothelial cells and was
Discussion
Although C. longa is found to have potent antioxidant and anti-inflammatory properties, very little is known in regard to its effect on the induction of cell adhesion molecules by TNF-α. In our study, ethyl acetate fraction of C. longa blocked TNF-α-induced expression of leukocyte adhesion molecules, ICAM-1, VCAM-1 and E-selectin. Further fractionation of the ethyl acetate fraction by TLC produced three main fractions (Fig. 2). Earlier fractionation of the alcoholic extract has also produced
Acknowledgements
We are grateful to Dr V.C. Jain for giving access to flow cytometer and to Dr B.S. Dwarkanath, and Mr J.S. Adhikari of INMAS, Delhi for helping us with the flow cytometric analysis. We thank Dr Eri S. Srivatsan of University of California School of Medicine, Los Angeles, California for providing us CRL1730 cell line.
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This work was supported by Council of Scientific and Industrial Research, India, and Department of Biotechnology, India. Babita Gupta is a recipient of CSIR fellowships.