Human interferon response

Ito X Kanzler H. Duramad O. Cao W, Liu YJ Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid pre-dendritic cells. Blood 2006 107 2423-2431. 

Interferons are natural proteins produced by the cells of the immune system in response to challenges by foreign agents such as viruses, parasites and tumor cells. Interferons assist the immune response by inhibiting viral replication within host cells. There are three major classes of interferons, interferon type I, interferon type II and interferon type III. They bind to a differen cell surface receptor complexes. The type I interferons in humans are IFN-o , IFN-jS and IFN- >. IFN-y is human interferon type II. All classes of interferon are important in fighting RNA virus infections and endogenous interferons are secreted when abnormally large amounts of dsRNA are found in a cell. 

Mechanism of Action. Although the details are unclear, imiquimod enhances the local production of interferons, tumour necrosis factor-alpha, and possibly other cytokines that produce antiviral responses. Hence, this drug does not act directly on the virus, but instead modulates the host (human) immune responses that have antiviral effects. 

Hermeling S, Schellekens H, Maas C, Gebbink MF, Crommelin DJ, Jiskoot W. Antibody response to aggregated human interferon alpha2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J Pharm Sci 2006 95(5) 1084-96. 

Interferon induction in normal and leukemic lymphocyte cultures with tilorone has been observed50. The interferon response observed in normal lymphocyte cultures appeared to be correlated with the toxic effect of tilorone. The effect observed in leukemic cultures required higher concentrations of tilorone, but, similarly, appeared to be related to cell viability. Tilorone has been reported to stimulate production of interferon by itself in mouse embryo fibroblasts and, in combination with poly rl poly rC/DEAE-dextran in mouse L929 cells51. Human foreskin fibroblasts were not stimulated. The degree of synergism between tilorone and the nucleotide-dextran complex was proportional to the concentrations of tilorone and poly rl/poly rC and was influenced by the times of addition of the compounds relative to each other. 

During periods of immune system response, for example, at times of infectious disease, cytochrome P450-dependent metabolism of xenobiotics is reduced. This effect is attributed to the production of interferon by the immune system as it responds to a challenge. Human interferon has been shown to suppress the metabolism of benzo [a] pyrene in laboratory animalsJ19 ... 

Interferons (IFNs) are potent cytokines that possess antiviral, immunomodulating, and antiproliferative activities. These proteins are synthesized by host cells in response to various inducers and, in turn, canse biochemical changes leading to an antiviral state in cells. Three major classes of human interferons with significant antiviral activity cnrrently... 

Fig. 4. Sequence comparison of IL-6, IFN-y, CNTF-responsive elements. Modified from Caldenhoven et al. (1994) and Bonni et al. (1993). Abbreviations rat a2M, the rat al macroglobulin hICAM-I, human ICAM-I hIRF-1, human interferon regulatory factor-1 hGBP, human GBP gene CNTF-RE, CNTF-responsive elements and IFN-y-activated site are also shown (Darnell et al., 1994).

P450 8A1 is constitutively expressed in human endothelial cells . The human CYP8A1 gene (chromosome 20) has 10 exons and has consensus sequences for Spl, AP-2, an interferon--/ response element, GATA NF, B, a CACCC box, glucocorticoid receptor, and a shear stress responsive element (GAGACC) . Whether or not all of these are functional and how they interact to maintain constitutive expression is not well understood yet. 

Wang R, Richie T L, Baraceros M F, et al. (2005). Boosting of DNA vaccine-elicited gamma interferon responses in humans by exposure to malaria parasites. Infect. Immun. 73 2863-2872. 

Zhu H, Cong JP, Shenk T (1997) Use of differential display analysis to assess the effect of human cytomegalovirus infection on the accumulation of cellular RNAs induction of interferon-responsive RNAs. Proc Natl Acad Sci USA 94 13985 13990... 

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