Biphasic Regulation of NF-κB Activity Underlies the Pro- and Anti-Inflammatory Actions of Nitric Oxide

Abstract

Expression of inducible NO synthase (iNOS) by macrophages is a prerequisite for the production of high output NO, which mediates many bactericidal and tumoricidal actions of these immune cells. The expression of iNOS in mammalian cells is governed predominantly by the transcription factor, NF-κB, which regulates the expression of many host defense proteins. In the present study, we characterize a novel, biphasic effect of NO on NF-κB activity in murine macrophages. This mechanism depends on the local concentration of NO and enables it both to up- and down-regulate the expression of host defense proteins including iNOS, cyclooxygenase-2, and IL-6. This biphasic activity of NO appears to play a pivotal role in the time course of activation of these immune cells and, by inference, in facilitating the initiation of a defense response against pathogenic stimuli and in its termination to limit tissue damage. This mechanism may explain at least in part the reported ability of NO to act in both a pro- and anti-inflammatory manner.

Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity

“…Several pieces of evidence indicate that the biological activities of NO may vary depending on the NO concentration (low or high doses exert pro-or anti-inflammatory effects, respectively), the cell types, enzymes, and transcription factors involved (26,27,30). Our data suggest that high concentrations of NO are affecting different cell types such as T cells, eosinophils, mast cells, and bronchial epithelial cells.…”

“…Since LPS up-regulates NOS2 activity (27) and NO is involved in the suppression of many immunoinflammatory processes (26,27,30,35), we compared the effects of LPS on the Th2-dominated intrapulmonary immune responses of NOS2 Ϫ/Ϫ with WT mice. Fig.…”

“…In addition, NOS2-derived NO might positively or negatively regulate cell signaling (26,27). We were therefore interested in investigating the effect of LPS on asthma-like responses in TLR4-deficient, IL-12 Ϫ/Ϫ , IFN-␥ Ϫ/Ϫ , or NOS2 Ϫ/Ϫ mouse strains.…”

Nitric oxide paradox in asthma

“…It is possible that these effects could be critically dependent on the concentration of NO generated (Connelly et al 2001).…”

“…It has been shown the NOS2-dependent catabolism of L-Arginine at low levels favor the production of peroxinitrite (ONOO -), a potent pro-inflammatory molecule (Xia & Zweier 1997, Xia et al 1998). Moreover, low local levels of NO promote the expression of pro-inflammatory proteins including COX2 and IL-6 (Connelly et al 2001).…”