Diarylheptanoids suppress expression of leukocyte adhesion molecules on human vascular endothelial cells
Introduction
The adhesion of circulating leukocytes to the vascular endothelium and their migration into tissues at sites of inflammation are essential events in various inflammation processes. These processes are mediated by the expression of leukocyte adhesion molecules on the surface of vascular endothelial cells Butcher, 1991, Carlos and Harlan, 1994, Springer, 1994. Major adhesion molecules are E-selectin (Bevilacqua et al., 1987), vascular cell adhesion molecule-1 (VCAM-1) (Osborn et al., 1989) and intercellular adhesion molecule-1 (ICAM-1) (Staunton et al., 1988), whose expression on endothelial cells is induced by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (Haraldsen et al., 1996). To reduce leukocyte adhesion to endothelial cells mediated by these adhesion molecules, various strategies have been used, such as the use of blocking antibodies for adhesion molecules (Barton et al., 1989), soluble forms of adhesion molecules (Gamble et al., 1990), synthetic peptide analogs based on the sequence of adhesion molecules (Fecondo et al., 1991), and agents that inhibit the upregulation of adhesion molecules (Boschelli et al., 1995).
It has been reported that phenolic diarylheptanoids such as yakuchinone B and demethyl-yakuchinone B derivatives of yakuchinones isolated from the fruit of Alpinia oxyphylla Miguel (Zingiberaceae), inhibit 5-lipoxygenase and cyclooxygenase Flynn and Rafferty, 1986, Iwakami et al., 1986, Kiuchi et al., 1992. Our recent study demonstrated that a novel phenolic diarylheptanoid derivative, 1-(3,5-dimethoxy-4-hydroxyphenyl)-7-phenylhept-1-en-3-one (YPE-01), inhibited 5-lipoxygenase and suppressed arachidonic acid- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema in mice (Yamazaki et al., 1998). The presence of a phenolic group in the diarylheptanoids is essential for the inhibition of 5-lipoxygenase and cyclooxygenase (Kiuchi et al., 1992). However, it has been reported that nonphenolic diarylheptanoids also have anti-inflammatory effects in various experimental models of inflammation in vivo Claeson et al., 1993, Claeson et al., 1996. Therefore, the mechanism of action of diarylheptanoids is not fully understood.
Since the adhesion of leukocytes to the vascular endothelium is an important step in inflammation, we hypothesized that the diarylheptanoids may exert part of their anti-inflammatory effects via suppression of the adhesion of leukocytes to endothelial cells. In the present study, we investigated the effects of several dialylheptanoids on the adhesion of leukocytes to human umbilical vein endothelial cells and the expression of leukocyte adhesion molecules on endothelial cells.
Section snippets
Materials
YPE-01, 1-(4-hydroxyphenyl-3-methoxy)-7-phenylhept-1-en-3-one (yakuchinone B), 1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (demethyl-yakuchinone B) and 1-(3,4,5-trimethoxy)-7-phenylhept-1-en-3-one (trimethoxy-YPE-01) (Fig. 1) were chemically synthesized by Yakult (Tokyo, Japan). Indomethacin and nordihydroguaiaretic acid were purchased from Sigma (St. Louis, MO). Other materials were purchased from the following sources: RPMI1640, TNF-α and TPA (Sigma); interleukin-1β (Genzyme, Cambridge,
Effects of diarylheptanoids on leukocyte adhesion to TNF-α-treated human umbilical vein endothelial cells
Since human U937 monocytic cells express lymphocyte-function associated antigen-1 (LFA-1), very late antigen-4 (VLA-4) and sialylated Lewis x glycoprotein (sLex), which are ligands for ICAM-1, VCAM-1 and E-selectin, respectively, they have been used in adhesion experiments with human umbilical vein endothelial cells (Hauser et al., 1993). Human EoL-1 eosinophilic cells also constitutively express high levels of LFA-1 and VLA-4 (Jung et al., 1994). We examined the effects of diarylheptanoids,
Discussion
It is well established that inhibitors of 5-lipoxygenase, inhibitors of 5-lipoxygenase activating protein and inhibitors of cyclooxygenase have anti-inflammatory properties Ford-Hutchinson et al., 1994, Vane and Botting, 1996. Therefore, most studies of the anti-inflammatory action of diarylheptanoids have focused on their inhibitory effects on 5-lypoxygenase and cyclooxygenase Flynn and Rafferty, 1986, Iwakami et al., 1986, Kiuchi et al., 1992, Yamazaki et al., 1998. The diarylheptanoids
Acknowledgements
We wish to thank Mr. Yoshitaka Tominaga and Ms. Yukiko Hosokawa for their excellent technical assistance.
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