OBJECTIVE The interferon-gamma (IFN-gamma)-mediated regulation of macrophage gene expression is of crucial importance in the pathogenesis of atherosclerosis. The mechanisms underlying the actions of IFN-gamma signaling in macrophages were investigated using monocyte chemoattractant protein (MCP)-1 as a model gene. METHODS AND RESULTS The IFN-gamma-induced expression of MCP-1 in macrophages wa...

STAT1 exists in phosphorylated (pSTAT1) and unphosphorylated (uSTAT1) forms each regulated by IFN-g . Although STAT1 is a key mediator of the IFN-g signaling pathway, an essential component of the host cancer immunosurveillance system, STAT1 is also overexpressed in certain human cancers where the functions of pSTAT1 and uSTAT1 are ill defined. Using amurinemodel of soft tissue sarcoma (STS), w...

Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addit...

STAT1 and STAT2 proteins are key mediators of type I and type III interferon (IFN) signaling, and are essential components of the cellular antiviral response and adaptive immunity. They associate with IFN regulatory factor 9 (IRF9) to form a heterotrimeric transcription factor complex known as ISGF3. The regulation of IFN-stimulated gene (ISG) expression has served as a model of JAK-STAT signal...

Interferon-gamma (IFNγ) plays a key role in macrophage activation, T helper and regulatory cell differentiation, defense against intracellular pathogens, tissue remodeling, and tumor surveillance. The diverse biological functions of IFNγ are mediated by direct activation of signal transducer and activator of transcription 1 (STAT1) as well as numerous downstream effector genes. Because a pertur...

IFNs orchestrate immune defense through induction of hundreds of genes. Small ubiquitin-like modifier (SUMO) is involved in various cellular functions, but little is known about its role in IFN responses. Prior work identified STAT1 SUMOylation as an important mode of regulation of IFN-γ signaling. In this study, we investigated the roles of SUMO in IFN signaling, gene expression, protein stabi...

The Fanconi anemia (FA) group C gene product (FANCC) functions to protect cells from cytotoxic and genotoxic effects of cross-linking agents. FANCC is also required for optimal activation of STAT1 in response to cytokine and growth factors and for suppressing cytokine-induced apoptosis by modulating the activity of double-stranded RNA-dependent protein kinase. Because not all FANCC mutations af...

In systemic inflammation induced by endotoxin (LPS), the macrophage produces the majority of the circulating NO metabolites. However, while the molecular pathways which up-regulate iNOS expression have been extensively studied in the macrophage, little is known of the parallel counterregulatory pathways which repress or inhibit macrophage iNOS expression. Using both in vivo and in vitro murine ...

NK cell functions were examined in mice with a targeted mutation of the STAT1 gene, an essential mediator of IFN signaling. Mice deficient in STAT1 displayed impaired basal NK cytolytic activity in vitro and were unable to reject transplanted tumors in vivo, despite the presence of normal numbers of NK cells. IL-12 enhanced NK-mediated cytolysis, but poly(I:C) did not, and a similar phenotype o...

STAT1 exists in phosphorylated (pSTAT1) and unphosphorylated (uSTAT1) forms each regulated by IFN-γ. Although STAT1 is a key mediator of the IFN-γ signaling pathway, an essential component of the host cancer immunosurveillance system, STAT1 is also overexpressed in certain human cancers where the functions of pSTAT1 and uSTAT1 are ill defined. Using a murine model of soft tissue sarcoma (STS), ...