EVects of anti-rheumatic herbal medicines on cellular adhesion molecules

Objective—To test the hypothesis whether herbal medicines ameliorate inflammatory diseases via the modulation of cellular adhesion molecules (CAMs). Methods—Human neutrophils, synovial fibroblasts, and endothelial cells were incubated with diVerent concentrations of Tripterygium Wilfordii Hook-f (TWH-f) or Tetrandrine in the presence or absence of interleukin 1 (IL1). The amount of soluble E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1) secreted by cells were determined by ELISA. The cell surface expression of these three CAMs was detected by flow cytometry. Results—TWH-f at high concentration (50 ng/ml) has a significant (p<0.05) inhibitory eVect on both the secretion and the expression of the cellular adhesion molecules. However, Tetrandrine did not demonstrate the same eVects. Conclusions—The cellular adhesion molecules of the endothelium and leucocytes may constitute excellent targets for the development of new anti-inflammation medicines. These results indicate that TWH could be a potential therapeutic agent in the treatment of inflammatory diseases. (Ann Rheum Dis 1999;58:366–371) Inflammation is characterised by the accumulation of leucocytes and other mesenchymal cells in response to attractant molecules at sites of injury or infection. Persistent inflammation without an identifiable antigen such as rheumatoid arthritis and systemic lupus erythematosus is often as destructive to the host as any invaded micro-organism. Once exposed to chemoattractants within the vasculature, leucocytes become activated and capable of adhering tightly to endothelium. In 1985, Bevilacqua and coworkers demonstrated that cytokines and endotoxin stimulated the endothelium to become more adhesive for leucocyte. Many of the adhesion molecules that mediate the interaction between endothelium and leucocyte and that are expressed on both these cell types have been isolated. There are three general classes of adhesion molecules present on leucocytes and endothelium: integrins, selectins, and members of the immunoglobulin superfamily of cell surface protein. Integrins and selectins on leucocytes mediate the adhesion of circulating cells to endothelium, whereas selectins and members of the immunoglobulin superfamily on the endothelium mediate their adherence for leucocyte. The CD11/CD18 glycoproteins are exclusively expressed on circulating leucocytes, and play an important part in the rapid adhesion of leucocytes to endothelial cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1), are well characterised endothelial cell ligands for the CD11/CD18 glycoproteins. E-selectin (ELAM-1) was the first inducible adhesive molecule that was originally shown to mediate the adhesion of neutrophils to cytokine or lipopolysaccharide activated endothelial cells. The explosion of information on the adhesion molecules that govern the emigration of leucocytes from blood vessels and their accumulation at loci of inflammation has completely changed our understanding of inflammation and may lead to new strategies in the treatment of acute and chronic inflammation. Previously published animal studies demonstrated that antibodies directed against adhesion molecules prevent experimental arthritis in animals. The results of new studies also suggest that measures designed to interfere with selectin mediated adhesion may diminish experimental arthritis. Tripterygium Wilfordii Hook-f (TWH) is a vine-like plant that grows in a wide area of south China. The structures of various constituents of TWH have been identified and include diterpenes, triterpenes, alkaloids, glycosides, b-sitosterol, daucosterol, dulcitol, and wilforonide. Some of these have antiinflammatory and immunosuppressive properties and are concentrated in the roots of the TWH plant. A refined extract from the root xylem of TWH, available in the Chinese pharmacopoeia as tablets for the long term treatment of rheumatoid arthritis and systemic lupus erythematosus, has recently been demonstrated to be eVective in suppression of renal disease and arthritis in MRL-lpr mice. In addition, tetrandrine (TTD), an extract of the tuberous root of the creeper Stephania tetrandra, a benzylisoquinoline with the empirical formula C38 H42O6N2 and molecular weight 622.73 daltons, is used in traditional Chinese medicine for the treatment of rheumatic diseases. However, both these two root extracted, historically famous, and clinical eVective anti-rheumatic medicines have an unclear mechanism of action. Previously, we have demonstrated that both TWH and TTD significantly inhibited interleukin 1â (IL1â) and tumour necrosis factor á (TNFá) release from monocyte. In this study, Ann Rheum Dis 1999;58:366–371 366 National Defence Medical Centre, Taiwan, ROC D M Chang Tri-Service General, Taipei, Taiwan, ROC S Y Kuo J H Lai M L Chang