Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil

Abstract

Study design: In vitro study on the effects of mycophenolate mofetil (MMF) on isolated human monocytes and endothelial cells. Objectives: 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. Setting: 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 mg/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-g, whereas the expression of sLeX was not impaired. Toxic effects were excluded by propidium-iodide staining and measurement of fluoresceindiacetate metabolism. Conclusion: 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. Sponsorship: This study was supported by the DFG (Ha 2721/1-3), the Paul und Ursula KleinStiftung and the Stiftung Friedrichsheim.

Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell

“…In fact, MPA may exert anti-inflammatory and antifibrotic effects in these cell types. In human umbilical chord vein endothelial cells (HUVEC), MPA attenuated the expression of adhesion molecules and incubation of monocytes and macrophages with MPA caused a reduced cell adhesion and a reduced cytokine and nitric oxide production by these cells [28,29]. Based on these findings, MPA delivery to EC and KC in the liver may even attenuate hepatic inflammation.…”

Effects of mycophenolic acid on endothelial cells

“…MMF may inhibit the activity of IMPDH and interfere the de novo guanosine nucleotides synthesis therefore suppress lymphocytes proliferation [9]. Moreover, MMF was found to suppress adhesion molecules expression in endothelial cells and inhibit leukocytes adhesion to endothelial cells [10,11]. These mechanisms may attribute to its efficacy of MMF in treatment of vasculitis, however, its mechanism of action remains not well known.…”

“…Inhibition of IMPDH leads to the depletion of intracellular guanosine nucleotides, thereafter suppresses the proliferation of both T and B lymphocytes. In addition, it has been reported [10,11] that MPA down-regulated adhesion molecules expression and reduced lymphocytes and monocytes adhesion, which may also contribute to the efficacy of MMF in the treatment of autoimmune diseases including systemic vasculitis. However, the mechanisms under the effect of MMF on vasculitis are still not fully understood.…”

Mechanisms of Action of Mycophenolate Mofetil in Preventing Acute and Chronic Allograft Rejection

“…MMF strongly suppressed VCAM-1, E-selectin, and P-selectin expression whereas cytokine-induced ICAM-1 upregulation was only slightly reduced (55) ( Table 1). MMF also has been shown to inhibit human monocyte attachment to ECs (56,57).…”