MOLECULAR MECHANISMS REGULATING iNOS EXPRESSION IN VARIOUS CELL TYPES

Abstract

Inducible nitric oxide synthase (iNOS) has been shown to be present in a variety of cell types, and nitric oxide (NO) has been implicated in a multitude of biological functions. The purpose of this review is twofold: (1) to provide a comprehensive table of cell types that produce NO together with the effects of agents used to study iNOS regulation, as a ready reference for the investigators in the field; and (2) to summarize recent observations dealing with iNOS signal transduction mechanisms. Initially, the major regulation of NO production was believed to occur at the transcription step, but now it is recognized that NO regulation can occur at the transcriptional, posttranscriptional, translational, and posttranslational level. There have been a number of studies of the regulation of iNOS in various cell types, often yielding conflicting results. The major emphasis of this review is on iNOS signal transduction mechanisms. For example, the role of JAK kinases and mitogen-activated protein (MAP) kinases in iNOS regulation is elaborated. In addition, species differences in the iNOS promoter region and the role of RNA structure in iNOS expression is discussed. The role MAP kinases play in translational regulation in addition to transcriptional regulation is emphasized. An analysis of the current data and suggestions for future studies are also presented.

IL-4 and interferon gamma regulate expression of inducible nitric oxide synthase in chronic lymphocytic leukemia cells

“…54 In HAEC, IL-4 prolongs expression of NOS2 mRNA and sustained activation of STAT1 which binds to a GAS promoter element. IL-4 has also been shown to induce transcription factor STAT6 binding to a GAS element in the monocytic cell line THP-1 55,58 and in the B cell line BL-2. 59 In B-CLL cells, STAT-1 is activated 60 and STAT-6 nuclear translocation is induced by IL-4.…”

“…29,54 The NOS2 promoter contains several interferon gamma activation sites (GAS elements), and IFN-␥ appears to regulate NOS2 expression primarily at the transcriptional level. 55 Alternatively, IL-4 has been shown to inhibit and induce NOS2 expression in macrophages. 56,57 In human airway epithelial cells (HAEC), IL-4 and IFN-␥ act together to promote NOS2 expression.…”

Piceatannol Prevents Lipopolysaccharide (LPS)‐Induced Nitric Oxide (NO) Production and Nuclear Factor (NF)‐κB Activation by Inhibiting IκB Kinase (IKK)

“…The expression of iNOS is induced by bacterial lipopolysaccharide (LPS) and an excess of NO is related to LPS-induced tissue damages (26). LPS-induced NO production is mediated by a series of signaling pathways, such as nuclear factor (NF)-κB and mitogen-activated protein (MAP) kinases including extracellular signal regulated kinase 1/2 (Erk1/2), p38 and stressactivated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) (32). In particular, NF-κB is a pivotal regulator of iNOS expression (24,32).…”

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions

“…24 The iNOS promoter contains several interferon-g activation sites (GAS elements) regulated by STAT-1 and STAT-6. 39 Recent reports have demonstrated that in B-CLL, STAT-1 is activated 40 and STAT-6 nuclear translocation is induced by IL-4 41 and controls iNOS expression at the transcription level. Our results show that IL-4 treatment is correlated to the inhibition of apoptotic cell death, the amplification of iNOS variants containing exons 13-16 and increased iNOS protein expression.…”