The enzyme nitric oxide synthase 2 (NOS2), often called inducible NOS, plays a central role in the inflammatory reactions that follow infection or tissue damage. NOS2 has been detected in virtually every cell type, and the NO it produces can perform both beneficial and detrimental actions. It is thus conceivable that regulatory mechanisms exist which control the timing and intensity of NO production by NOS2 in order to outweigh protective effects against detrimental ones. Since cyclic AMP inhibits numerous immunological reactions, studies have been carried out to determine whether cAMP-dependent pathways could inhibit NOS2 expression as well. Pharmacological studies in cultured cells show that, depending on the cell type examined, increased cAMP can exert opposite effects on the endotoxin- or cytokine-induced expression of NOS2, being either stimulatory or inhibitory in macrophages, stimulatory in adipocytes, smooth muscle, skeletal muscle, and brain endothelial cells, and inhibitory in pancreatic, liver, and brain glial cells. Regulation of NOS2 gene transcription appears to be the primary mechanism of action of cAMP, and whether it is stimulatory or inhibitory hinges on the cell-specific regulation of transcription factors including CREB, NF-kappaB, and C/EBP. Cyclic AMP must therefore be considered a modulator rather than a suppressor of NOS2 expression. This review summarizes evidence derived from in vitro studies, considers regulation of NOS2 by cAMP in vivo, and discusses possible therapeutic applications of cAMP treatment.-Galea, E., Feinstein, D. L. Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP.