Interferon-γ regulation of the human mimecan promoter

The IFNs are a family of secreted glycoproteins that play roles in regulation of antiviral, antiproliferative, and immunomodulatory responses in vertebrate cells. Two types of IFNs have been described, the type I IFNs (α, β, ω, and τ) that are produced by leukocytes and fibroblasts, and the type II IFN (γ) that is produced by T-lymphocytes and natural killer cells in response to infections by viruses and bacteria, as well as in response to noninfectious agents [1,2]. Both types of IFNs exert their biological effects through the signal transduction pathways that initiate by binding of IFNs to their corresponding cell surface receptors; interferon α receptor (IFNAR) for all type I IFNs and interferon γ receptor (IFNGR) for type II IFN. IFN receptors have been detected in almost all mammalian cell types [3,4]. Binding of IFNs with their receptors leads to activation of the Janus kinases (Jaks), which in turn leads to tyrosine phosphorylation and activation of signal transducers and activators of transcription (Stat) proteins [5]. Activated Stat-1 proteins form dimers that translocate to the nucleus and selectively regulate the genes containing the GAS element in their promoters. Heterotrimers of Stat-1, Stat2 and p48 (known as ISGF3γ and IRF9) also translocate to the nucleus and results in regulation of genes containing ISRE in their promoters [1,2]. The interferon regulatory factors also are induced by these pathways and form a group of secondary transcription factors that bind to ISRE sequences and affect transcription of different sets of genes, depending on the cell type and the nature of cellular stimuli [6]. In addition to the pathways described above, other signaling proteins and transcription factors have been shown to participate in the IFNinduced cellular responses. These include p38 mitogen-activated protein kinase (MAPK), transcription factors CBP/p300, USF1 and NF-κB, shown to act as co-activators, and the class II transactivator (CIITA) that can act as a suppressor of transcription [7-11]. IFNs are known to affect the expression of more than 50 cellular genes. Among IFN-regulatable genes are several members of the proteoglycan gene family, including aggrecan, perlecan and glypican, members of the small leucine-rich proteoglycan gene family, including decorin and © 2003 Molecular Vision