Positive effects of biological response modifiers on cancer cells are usually measured using markers for increased immunogenicity as well as those for increased differentiation of the cells. An increase in levels of HLA class I antigens and the adult (beta) globin molecules are two such markers that may be used to assess the effect of modulators like interferons on the K562 erythroleukaemia cell line. Although interferon mediated up regulation of gene expression is thought to be primarily regulated by binding of proteins to the Interferon responsive cis elements in the promoters of IFN responsive genes, recent evidence has shown the induction of other transcriptional activators in response to IFN treatment. We present evidence for one such instance wherein up regulation of HLA class I and beta globin gene transcription are accompanied by induction of binding activities similar to RXR beta and kB proteins in K562 cells.
[Show abstract][Hide abstract] ABSTRACT: IFN-alpha-2b, known as potent immune modulator, can either inhibit or enhance immune cell activity within the tightly regulated microenvironment of inflammation, depending upon the concentration of the cytokine and the activation stage of the cell. Chemokine receptors, which not only mediate chemotaxis of immune cells to the site of inflammation but also affect cellular activation by transferring corresponding signals, represent yet another level of immune regulation. Here we demonstrate that IFN-alpha increases the expression of CCR1 and CCR3 in primary mononuclear phagocytes, as well as in the monocytoid cell line U937. Enhanced receptor mRNA expression correlated with functional readouts such as increased intracellular calcium mobilization and cell migration in response to ligands. Expression of CCR2b, CCR4, CCR5, and CXCR4 was unchanged or decreased after IFN-alpha treatment. These observations indicate a differentially regulated cellular signaling relationship of IFN-alpha pathways and chemokine receptor expression. We also provide evidence that, under these conditions, IFN-alpha treatment increased the expression of CD95 (Fas, Apo1), resulting in enhanced susceptibility to apoptosis. Taken together, these data add important information for the rational application of IFN-alpha (2b) in immune and cancer therapies.
The Journal of Immunology 10/1999; 163(6):3169-75. · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Major histocompatibility complex (MHC) is a conglomerate of genes that play an important role in recognition of self and nonself. These genes are under tight control. In this review we have discussed the transcription processes regulating MHC gene expression. Various biological or chemical modulators can modulate MHC gene expression. The promoter region of class I genes can be activated through several pathways. Hence, these genes are not typical "domestic" genes. Extensive studies on regulation of MHC class I expression, using transfection techniques and transgenic animal models, have resulted in identification of various cis-acting sequences involved in positive and negative regulation of class I genes. Work is in progress to identify the transacting proteins that bind to these sites and to delineate the mechanisms that regulate constitutive and inducible expression of class I genes in normal and diseased cells. It has been seen that various biological molecules (IFN, GM-CSF, IL-2) and other chemicals up-regulate the MHC expression. If the exact mechanisms are known by which the expression of class I genes is up regulated, the efforts can be made to balance the beneficial and toxic effects of biological molecules with one another, which may facilitate the use of combination of these molecules in subpharmacological doses (to eliminate toxicity) for early and better management of neoplastic diseases, as it is well-known that during malignancy MHC gene expression is down-regulated. In the future, the use of transgenic and knockout mice will be useful in acquiring a better understanding, which may further help in cancer therapy.
Journal of Hematotherapy & Stem Cell Research 01/2001; 9(6):795-812. DOI:10.1089/152581600750062237
[Show abstract][Hide abstract] ABSTRACT: Previous experiments have suggested that induction of the beta-R1 gene by interferon (IFN)-beta required transcription factor ISGF-3 (IFN-stimulated gene factor-3) and an additional component. We now provide evidence that nuclear factor-kappaB (NF-kappaB) can serve as this component. Site-directed mutagenesis of an NF-kappaB binding site in the beta-R1 promoter or over-expression of an IkappaBalpha super-repressor abrogated IFN-beta-mediated induction of a beta-R1 promoter-reporter. IFN-beta treatment did not augment abundance of NF-kappaB but did lead to phosphorylation of the p65 NF-kappaB subunit. It is proposed that IFN-beta-mediated enhancement of the transactivation competence of NF-kappaB components is required for inducible transcription of the beta-R1 promoter. These results provide a novel insight into the role of NF-kappaB in the transcriptional response to IFN-beta.
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