Prostacyclin inhibits the production of MMP-9 induced by phorbol ester through protein kinase A activation, but does not affect the production of MMP-2 in human cultured mesangial cells

Background/Aims: The imbalance between degradation and synthesis of the glo merular extracellular matrix (ECM) causes glomerular sclerosis in various t ypes of glomerulonephritis. We investigated the effect of prostacyclin, whi ch is an inflammatory mediator, on the production of matrix metalloproteina se (MMP)-9 and MMP-2 in hu man cu Itu red mesangial cells. The synthesis of Jun proteins and Ets-l proteins, which are related with MMP-9 gene, was al so studied. Methods: The production of MMP-9 and MMP-2 was investigated by gelatin zymography. Western blotting was undertaken to analyze the protein synthesis of Jun and Ets-l. Results: Prostacyclin inhibited the production of MMP-9 induced by phorbol ester. The inhibitory effect by prostacyclin wa s reversed in part by the pretreatment with an inhibitor of protein kinase A, such as H-89. Forskolin also inhibited the production of MMP-9. The prod uction of MMP-2 was constitutionally seen and was not influenced by prostac yclin and forskolin. The synthesis of Jun protein augmented by phorbol este r was suppressed by prostacyclin. Ets-l protein was constitutionally synthe sized and was not affected by phorbol ester and prostacyclin. Conclusion: P rostacyclin plays an important role in inflammatory glomerular disorders by regulating the metabolism of ECM. The production of MMP-9 and MMP-2 may be under the different control pathways. Copyright (C) 2001 S. Karger AG, Bas el.