Protein kinase C-mediated regulation of inducible nitric oxide synthase expression in cultured microglial cells

Nitric oxide (NO) has been implicated in a number of important brain functi ons, such as long-term potentiation (LTP) and long-ten depression (LTD), an d in events associated with neurodegeneration and neuroprotection. In respo nse to brain injury or disease NO production is increased by an inducible e nzyme (iNOS), which is only expressed under these conditions. Activated mic roglia are a major cellular source of NOS in brain. Due to the important ro le of iNOS in brain injury and disease, a detailed understanding of intrace llular events triggering the expression of iNOS in microglia would facilita te pharmacotherapeutic approaches. It is shown here, that iNOS mRNA, protei n and NO product are induced in cultured microglia by lipopolysaccharide (L PS). This induction is reduced by a number of substances elevating intracel lular cyclic AMP levels. It is unabated, however, in the presence of substa nces inhibiting cyclooxygenase-l and/or cyclooxygenase-2 (e.g., acetyl sali cylic acid, SC 58125, L 745337), but is decreased by approx. 50% with PDTC, a scavenger of reactive oxygen intermediates (ROI) that inhibits nuclear f actor KB (NF-KB) activation. Furthermore, inhibitors of protein kinase C (P KC) strongly inhibit iNOS mRNA and protein induction. PKC, therefore, const itutes a major second messenger component (besides NF-KB) in the signaling pathway regulating iNOS expression in microglia. (C) 1998 Elsevier Science B.V. All rights reserved.