Regulation of the Expression of Inducible Nitric Oxide Synthase

Abstract

Nitric oxide (NO), generated by the inducible isoform of nitric oxide synthase (iNOS), has been described to have beneficial microbicidal, antiviral, antiparasital, immunomodulatory, and antitumoral effects. However, aberrant iNOS induction at the wrong place or at the wrong time has detrimental consequences and seems to be involved in the pathophysiology of several human diseases. iNOS is primarily regulated at the expression level by transcriptional and post-transcriptional mechanisms. iNOS expression can be induced in many cell types with suitable agents such as bacterial lipopolysaccharides (LPS), cytokines, and other compounds. Pathways resulting in the induction of iNOS expression may vary in different cells or different species. Activation of the transcription factors NF-kappaB and STAT-1alpha, and thereby activation of the iNOS promoter, seems to be an essential step for iNOS induction in most cells. However, at least in the human system, also post-transcriptional mechanism are critically involved in the regulation of iNOS expression. The induction of iNOS can be inhibited by a wide variety of immunomodulatory compounds acting at the transcriptional levels and/or post-transcriptionally.

Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor

“…2 D and G). Because both iNos and Il18 are induced by proinflammatory stimuli, including lipopolysaccharide and various cytokines (32,33), this likely reflects regulation of these genes by additional signaling pathways that are activated by BDL.…”

Deficiency of XIAP Leads to Sensitization for Chlamydophila pneumoniae Pulmonary Infection and Dysregulation of Innate Immune Response in Mice

“…Our data and previous work (34) strongly suggests that the XIAPmediated induction of iNOS in response to these stimuli is an important parameter to resolve C. pneumoniae pulmonary infection. Transcriptional regulation of iNOS is very complex, and more than 15 different consensus binding sites for transcription factors have been identified in the promoter region of the iNOS gene (39). One of the factors regulating iNOS transcription is NF-B, which is not only controlled by cIAP-1 and cIAP-2 (19) but also by XIAP.…”

Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

“…In spite of the demonstrated connection between MAPK activation and iNOS expression, the events that lie in between remain largely unknown. The large, complex iNOS promoter is known to contain binding sites for activator protein-1 (AP-1), nuclear factor-kB (NF-kB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-1a (STAT-1a), cAMP-responsive element binding protein (CREB), and CCAAT-enhancer box binding protein (C/EBP), to name a few (Kleinert et al, 2003). Indeed, evidence exists in several cell types for the involvement of NF-kB in mediating the regulation of iNOS by ERK, and these findings may be relevant to melanoma (Kristof et al, 2001;Liu et al, 2002;Jiang et al, 2004).…”