Mycophenolic acid influences T helper 2 (Th2) cytokine induced expression of intercellular cell adhesion molecule-1 (ICAM-1) on human endothelial cells.
A possible synergistic effect of mycophenolic acid (MPA) and the immunosuppressive cytokines IL-4, IL-10 and IL-13 was investigated in human umbilical vein endothelial cells (HUVEC). These cytokines, which are produced by Th2-lymphocytes, were shown to induce the expression of vascular cell adhesion molecule-1 (VCAM-1) and production of IL-6 in endothelial cells. In this study we found IL-4 to induce both intercellular cell adhesion molecule-1 (ICAM-1) and VCAM-1 expression, whereas IL-13 induced VCAM-1 only. The surface expression of E-selectin was not influenced by any of the cytokines tested. MPA on its own led to statistically significant ICAM-1 expression on HUVEC. The combination of MPA with IL-4 led to a significant ICAM-1 expression in an additive manner compared to the cytokine alone. In contrast, MPA neither induced VCAM-1 nor did it influence the effects of IL-4 and IL-13 on VCAM-1 expression. A clinically relevant concentration of mycophenolic acid (10 micromol/l) decreased intracellular guanosine-5'-triphosphate (GTP) levels significantly. Since intracellular nucleotides are responsible for the glycosylation of proteins, a disturbance of the endothelial nucleotide balance could be responsible for the effects of MPA on ICAM-1. Guanine and guanosine prevented and partially reversed the actions of MPA, on both intracellular GTP and ICAM-1 expression, which strongly implies that MPA by interfering with nucleotide metabolism, affects the adhesive properties of endothelial cells, and by acting synergistically with IL-4 probably influences Th2 cytokine effects.
Weigel
G
G
Department of Cardiothoracic Surgery, University Vienna, Austria. guenter.weigel@akh-wien.ac.at
Bertalanffy
P
P
Dubsky
P
P
Griesmacher
A
A
Wolner
E
E
D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007378:Interleukins / Q000502:physiology*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism
D015815:Cell Adhesion Molecules; D007378:Interleukins; D018799:Intercellular Adhesion Molecule-1; D006160:Guanosine Triphosphate; D009173:Mycophenolic Acid