Transcriptional Regulation of the Inflammatory Nitric Oxide Synthase Gene: Convergence of Cytosolic and Nuclear Signals

The enzyme nitric oxide synthase 2 (NOS2, or inducible NOS) is expressed by numerous cell types during inflammatory reactions in vivo and in vitro. The NO derived from NOS2 exerts beneficial actions such as the elimination of microorganisms, the reduction of thrombosis, and the increase of blood supply to injured tissues. However, NO released in excess can cause tissue damage, contributing to diseases like septic shock, rheumatoid arthritis, cerebral ischemia, multiple sclerosis, and diabetes. It is well established that induction of the NOS2 protein by inflammatory stimuli is primarily regulated at the level of gene transcription, and that the interaction of the transcription factor NFkB and its inhibitory protein, IkB, play a central role in this process. In addition, recent pharmacological evidence implicates the mitogen activated protein kinase (MAPK) pathways as a second key mediator of the cytokine-induced transcription of NOS2. In turn, the induction of the NOS2 gene can be either inhibited or potentiated, depending on the cell type, by cyclic AMP-dependent pathways, acting via transcription factors like CREB, NFkB and C/EBP. Finally, the heat shock response has recently emerged as a second potent means of suppressing both the cytokine and endotoxin-dependent activation of NOS2 transcription. The mechanism responsible for this suppression appears to be the prevention of NFkB activation. These observations suggest that the transcription of the NOS2 gene is tightly regulated by several cascades of cytoplasmic and nuclear reactions, thus providing a wide array of biological and therapeutical targets to control the production of NO to avoid its detrimental actions.