Affiliations: Department of Anesthesiology, University of Illinois
at Chicago, Chicago, IL, USA | Department of Neurology, Medical University of South
Carolina, Charleston, SC, USA
Note: [] Address for correspondence: Elena Galea Anesthesiology M/C519
University of Illinois at Chicago 1819 W. Polk St Chicago, IL 60612 Voice:
312-996-9933 Fax: 312-996-9680 E-mail: [email protected]
Note: []
Abstract: 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.
