Curcuma longa inhibits TNF-α induced expression of adhesion molecules on human umbilical vein endothelial cells

doi:10.1016/S0192-0561(99)00050-8

International Journal of Immunopharmacology

Volume 21, Issue 11, November 1999, Pages 745-757

International Journa...

https://doi.org/10.1016/S0192-0561(99)00050-8 Get rights and content

Abstract

Identification of non-steroidal anti-inflammatory small molecules is very important for the development of anti-inflammatory drugs. We demonstrate here that out of three compounds, viz diferuloylmethane, p-coumaroylferuloylmethane and di-p-coumaroylmethane, present in the ethyl acetate extract of Curcuma longa, diferuloylmethane is most potent in inhibiting TNF-α induced expression of ICAM-1, VCAM-1 and E-selectin on human umbilical vein endothelial cells. The inhibition by diferuloylmethane is time dependent and is reversible. By using RT-PCR, we demonstrate that it inhibits the induction of steady state transcript levels of ICAM-1, VCAM-1 and E-selectin, and therefore it may interfere with the transcription of their genes. As diferuloylmethane significantly blocks the cytokine induced transcript levels for the leukocyte adhesion molecules, it may be interfering at an early stage of signalling event induced by TNF-α.

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.

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Curcuma longa inhibits TNF-α induced expression of adhesion molecules on human umbilical vein endothelial cells☆

Abstract

Introduction

Section snippets

Materials

Ethyl acetate extract of C. longa inhibits TNF-α induced ICAM-1 expression on endothelial cells in a dose dependent manner

Discussion

Acknowledgements

Cell

Immunol. Today

Immunol. Today

Anal. Biochem.

Cell

J. Biol. Chem.

FEBS Lett.

Cell

Cell

Immunity

Biochem. Pharmacol.

Anti-inflammatory and anti-arthritic activity of volatile oil of Curcuma longa

Ind. J. Med. Res.

Comparison of anti-inflammatory activity of various extracts of Curcuma longa

Indian J. Med. Res.

Cytokine regulation of endothelial cell function

FASEB