TETRAHYDROBIOPTERIN MODULATES CYCLOOXYGENASE-2 EXPRESSION IN HUMAN MESANGIAL CELLS

Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under i nflammatory conditions. The newly synthesized BH4 serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In hu man mesangial cells (HMC), BH4 is also a limiting factor for NOS2 expr ession. In this study we show that Be availability can also play a mod ulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Sup plementing HMC with the BH4 donor sepiapterin potentiated IL-1 beta/TN F-alpha-induced COX-2 expression by approximately 2-fold. This effect was abolished by methotrexate. In contrast, the NOS inhibitor L-NAME a nd the soluble guanylate cyclase inhibitor ODQ did not block sepiapter in amplification of COX-2 expression. Moreover, sepiapterin was found to modulate the tyrosine phosphorylation of several cellular substrate s, an early event which occurred well before the induction of NOS2 cou ld be evidenced. These findings suggest a role for BH4 in the modulati on of mesangial cell responses to pro-inflammatory stimuli. (C) 1997 A cademic Press.