Differential regulation of inducible nitric oxide synthase and cytokine gene expression by forskolin and dibutyryl-cAMP in lipopolysaccharide-stimulated murine BV2 microglial cells

This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate the expression of several cytokines and inducible nitric oxide synthase (iNOS) in a different manner. Both dbcAMP and forskolin repressed lipopolysaccharide (LPS)-induced TNF-alpha expression and enhanced anti-inflammatory cytokine IL-10 level in the BV2 microglia. In contrast, they differentially regulated the iNOS, IL-6 and IL-1beta expression levels. DbcAMP increased the IL-1beta level without affecting either the IL-6 or iNOS expression, whereas forskolin repressed the IL-6 and iNOS expression level without affecting IL-1beta in the LPS-stimulated microglia. Treatment with H89, a specific inhibitor of protein kinase A (PKA), revealed that an enhancement in the IL-10 and IL-1beta levels by dbcAMP or forskolin totally depends on the PKA pathway, while changes in the other cytokines and iNOS are independent or only partially dependent on the PKA pathway. These results suggest the diverse regulation of the inflammatory reactions depending on different cAMP elevating agents. (C) 2003 Elsevier Ireland Ltd. All rights reserved.