Interleukin-1-induced cyclooxygenase 2 expression is suppressed by cyclosporin A in rat mesangial cells

The immunosuppressive drug cyclosporin A (CsA) has considerable nephrotoxic side effects which seem to be related to its interference with the synthesis of vasoactive prostanoids. Therefore, the molecular mechanism of the effect of CsA on the synthesis of prostaglandin E2 (PGE2) was investigated in rat renal mesangial cells (RMC). CsA effectively inhibited the PGE2 synthesis induced by inflammatory cytokines such as interleukin 1 (IL-1) or tumor necrosis alpha (TNF alpha). The induction by IL-1 and the inhibition by CsA were reflected in the enzyme activity of the cyclooxygenase. The changes in activity could be correlated with the expression of the inducible cyclooxygenase isoform (COX2), which is characterized by its 4.4 kb mRNA: the expression of this enzyme was enhanced by IL-1 and suppressed by CsA on the mRNA and protein level as determined by Northern and Western blot analyses. Suppression of COX2 mRNA was also observed when the message was induced by LPS or ionophore A23187. The expression of the basal cyclooxygenase isoform (COX1), which was constitutively expressed in proliferating mesangial cells, was not affected by IL-1 or CsA. Interferon gamma, which did not induce prostaglandin synthesis or influence COX mRNA expression, augmented the expression of MHC antigens in RMC. This induction was insensitive to CsA treatment. We could thus show that the inducible cyclooxygenase isoform in mesangial cells is a molecular target for CsA providing a possible mechanism for the interference of the drug with the balance of vasoactive prostanoids.