Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil.
METHODS
In vitro study on the effects of mycophenolate mofetil (MMF) on isolated human monocytes and endothelial cells.


OBJECTIVE
Haematogenous macrophages play an essential role in the development of secondary damage following spinal cord injury (SCI), and there is evidence that the use of immunosuppressants such as MMF can reduce monocyte invasion and neuronal damage.


METHODS
University Hospital for Orthopaedic Surgery, Frankfurt am Main, Germany.


METHODS
The effects of MMF on the adhesion of human monocytes to human umbilical vein endothelial cells (HUVEC), monocyte binding to immobilised E-selectin, and monocyte expression of intercellular adhesion molecule (ICAM)-1, sialyl Lewis X (sLeX) and major histocompatibility complex (MHC)-II were studied. The binding of monocytes to E-selectin was examined by using purified and immobilised E-selectin fusion protein. Adhesion molecule expression was investigated by flow cytometry.


RESULTS
The binding of monocytes to HUVEC was significantly reduced by 30.1% after treatment of monocytes with MMF (10 microg/ml), whereas the pretreatment of HUVEC with MMF did not result in significant changes in monocyte adhesion. MMF forcefully inhibited monocyte binding to immobilised E-selectin by 55.7%. Furthermore, MMF significantly inhibited the upregulation of ICAM-1- and MHC-II-expression on monocytes stimulated with either lipopolysaccharide or interferon-gamma, whereas the expression of sLeX was not impaired. Toxic effects were excluded by propidium-iodide staining and measurement of fluorescein-diacetate metabolism.


CONCLUSIONS
MMF can downregulate important monocytic adhesion molecules and inhibits monocyte adhesion to endothelial cells, thus indicating that treatment with MMF could be beneficial after SCI.


BACKGROUND
This study was supported by the DFG (Ha 2721/1-3), the Paul und Ursula Klein-Stiftung and the Stiftung Friedrichsheim.
Glomsda
B A
BA
University Hospital for Orthopaedic Surgery Friedrichsheim, Frankfurt am Main, Germany.
Blaheta
R A
RA
Hailer
N P
NP
D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016256:Lewis X Antigen / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011419:Propidium / Q000378:metabolism; D014157:Transcription Factors; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D019040:E-Selectin; D007166:Immunosuppressive Agents; D016256:Lewis X Antigen; D008070:Lipopolysaccharides; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; C077171:HIVEP2 protein, human; D011419:Propidium; D009173:Mycophenolic Acid