Inhibition of Inducible Nitric Oxide Synthase Expression by Interferons α and β in Bovine Retinal Pigmented Epithelial Cells

Anti-inflammatory action of type I interferons deduced from mice expressing interferon β

“…Some investigators reported a potentiation of the activation process, 37,44 and others described an anti-inflammatory contribution. 5,7,22,45 However, these data can be concealed if the nature of the pro-inflammatory stimuli used to activate macrophages and the time at which macrophages produce endogenous type I IFNs synthesis are considered. Challenge of macro-phages with LPS, in the absence of IFN-␥ synergism, is independent of the action of IFN-␣/␤ 37,44 (and this work); however, macrophage activation in the presence of IFN-␥ is significantly abrogated by type I IFNs.…”

“…Challenge of macro-phages with LPS, in the absence of IFN-␥ synergism, is independent of the action of IFN-␣/␤ 37,44 (and this work); however, macrophage activation in the presence of IFN-␥ is significantly abrogated by type I IFNs. 5,22 Moreover, following viral infection (for example with flavivirus), an abrogation has been shown of the expression of iNOS in macrophages challenged with IFN-␥ and TNF-␣, due to the overproduction of IFN-␣/␤ by infected cells. 46,47 Synthesis of IFN-␣/␤ by cells stimulated with pro-inflammatory cytokines is required for the effective expression of iNOS, as deduced by the observation that inhibition of IFN-␣/␤ activity with neutralizing antibodies abolished the induction of iNOS in animals infected with intracellular microbes, giving a phenotype similar to that of animals with a null mutation of iNOS.…”

“…20 In this vein, inhibition by type I IFNs of iNOS expression has been described in macrophages stimulated in vitro with IFN-␥, and this has been explained in terms of the antagonism between type I and type II IFNs. 5,7,[21][22][23] Indeed, the antagonism between type I and II IFNs has been observed in other cells, for example in the expression of MHC class II proteins, where type I IFNs down-regulate the process. 24 Regarding the expression of iNOS in the macrophage, multiple sites for the binding of factors modulated by IFN-␥ and type I IFNs have been recognized in the promoter region of the gene, including IFN-stimulated response element (ISRE), ␥-activated site (GAS) and IFNregulatory factor element (IRF-E).…”

“…Interestingly, these effects were observed only during the initial 2-h period of stimulation, indicating that type I IFNs inhibited the recruitment or the function of the transcription factors responsible for the activation of the iNOS promoter, but they did not affect the stability of the iNOS mRNA and protein. 5,22 Keeping in mind this perspective, it is reasonable to develop pharmacological approaches intended to regulate the function of inflammatory cells, based on the administration of type I IFN. In this regard, taking advantage of the development of transgenic mice expressing a human IFN-␤ gene (hIFN-␤) in ␤-cells under the control of the rat insulin I promoter, 25 we evaluated the ability of elicited macrophages from these animals to respond after pro-inflammatory stimulation.…”

Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-κB

“…Functional ISRE and GAS elements were identified in the miNOS promoter (23)(24)(25). Recent experiments in the murine system indicate a complex role for IFN-␣͞␤ and Jak 2 kinase in cytokine-induced miNOS transcription (26)(27)(28). Cotransfection of a dominant-negative Jak 2 kinase with a miNOS promoter-reporter revealed that Jak 2 functions as an activator or a repressor of miNOS transcription depending on the cell type.…”