Mycophenolic acid affects basic functions of human keratinocytes in the IMPDH-dependent manner

Abstract

Clinical studies suggest that the immunosuppressant MPA is associated with impaired wound healing. It is believed that the main cause of impairment is the inhibition of inflammatory response. However, it is unknown whether MPA may directly affect epidermal cells. The aim of our study was to examine the direct influence of mycophenolic acid, the selective blocker of de novo purine synthesis, on human epidermal keratinocyte morphology, proliferation, motile activity, and differentiation in in vitro culture. The number of keratinocytes cultured in the presence of MPA was counted and cell motility was measured by a time-lapse computer-aided method. Cell morphology was determined by flow and image cytometry methods. Real-time RT-PCR analysis was employed to investigate the expression of markers of differentiation. We showed that MPA induces irreversible inhibition of cell proliferation, causes cell enlargement and impairs cell locomotion in a time-dependent manner. The level of expression of differentiation markers was significantly reduced by MPA treatment. All these effects were reversed by the addition of guanine. Our results indicated that MPA impairs basic functions of human skin keratinocytes via intracellular guanosine nucleotide depletion, which may be directly reflected in wound healing problems in patients treated with this immunosuppressant.