IFN-stimulated response element

S. J. Haque and B. R. Williams. Identification and characterization of an interferon (IFN)-stimulated response element-IFN-stimulated gene factor 3-independent signaling pathway for IFN-alpha. J Biol Chem. 269 (30), 19523-19529, 1994. 

All IFN-stimulated genes are characterized by the upstream presence of an interferon-stimulated response element (ISRE). Signal transduction culminates in the binding of specific regulatory factors to the ISRE, which stimulates RNA polymerase Il-mediated transcription of... 

The three activated STATs disengage from the receptor and bind to the cytoplasmic protein, p48. This entire complex translocates to the nucleus, where it interacts directly with upstream regulatory regions of IFN-sensitive genes. These nucleotide sequences are termed interferon-stimulated response elements (ISREs). This induces/augments expression of specific genes, as discussed later. 

These last factors also up-regulate hBD-2 secretion by the intestinal epithelial cell lineage Caco-2 stimulated with probiotic bacteria [176]. Although not yet demonstrated experimentally, mammalian cathelicidins may respond to inflammatory stimuli, since the 5 flanking sequences upstream of the peptide coding sequence have several potential consensus sequences for transcription factors involved in inflammatory response, sueh as NF-kB, NF-IL-6, acute-phase response factor and IFN-y response elements [147,170,177]. 

Takeda K, KamanakaM, TanakaT, Kishimoto T, Akira S. Impaired IL-13-mediated functions of macrophages in Stat6-deflcientmice. J Immunol 1996 157 3220-3222. Ohmori Y, Hamilton TA. The interferon-stimulated response element and a kappa B site mediate synergistic induction of murine IP-10 gene transcription by IFN-gamma and TNF-alpha. J Immunol 1995 154 5235-5244. 

Gene expression experiments revealed that HCMV blocks IFN-ot-stimulated ISGF3-dependent (MHC class I, 2, 5 -OAS, and MxA) and ISGF3-independent (IRF-1) gene expression in infected fibroblasts and ECs (Miller et al. 1999). EMSA analyses, utilizing a DNA-binding element that binds STAT-1 homodimers and STAT-1/STAT-2 heterodimers, revealed that IFN-ot-stimulated transcription factor activation was blocked in HCMV-infected cells (Miller et al. 1999). Immunoprecipitation experiments demonstrated that IFN-ot-stimulated tyrosine phosphorylation was also blocked in HCMV-infected cells, a cellular phenotype that correlates with decreased JAKl protein (Miller et al. 1999). Thus the HCMV-mediated decrease of JAKl protein may mediate disruption of IFN-ot-stimulated responses in a manner analogous to the defect in the IFN-y pathway. 

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