Immune Interferons

Interferon-7 was the first secretory product of T cells to be discovered when it was found that supernatants derived from suspensions of T cells that had been treated with mitogenic agents could activate macrophages. This macrophage activating factor , subsequently found to interfere with the replication of viruses, was thus named interferon. The production of this compound, associated with delayed-type hypersensitivity and cell-mediated immunity, was termed immune interferon or type II interferon. With the discovery of other lymphokines with interferon-like activity (interferon-a and -j3), the compound was finally designated interferon-7. 

Cassatella, M. A., Hartman, L., Perussia, B., Trinchieri, G. (1989). Tumor necrosis factor and immune interferon synergistically induce cytochrome b.245 heavy-chain gene expression and nicotinamide-adenine dinucleotide phosphate hydrogenase oxidase in human leukemic myeloid cells. J. Clin. Invest. 83,1570-9. 

Perussia, B., Dayton, E. T., Lazarus, R., Fanning, V., Trinchieri, G. (1983). Immune interferon induces the receptor for monomeric IgGl on human monocytic and myeloid cells. J. Exp. Med. 158,1092-113. 

Interferons were originally discovered as proteins that interfered with virus replication. When mice were injected with antibodies to interferons, they became markedly susceptible to virus-mediated disease, including virus-related tumour induction. Interferons can be detected at low levels in most human tissues, but amounts increase upon infection with viruses, bacteria, protozoa, and exposure to certain growth factors. Interferons were initially classified according to the cellular source, but recent nomenclature is based primarily on sequencing data. Thus leukocyte interferon (a mixture of proteins) is now known as interferon alfa, fibroblast interferon as interferon beta, and immune interferon as interferon gamma. 

Pober JS, GimbroneMA, Jr., LapierreLA, MendrickDL, Fiers W, Rothlein R, Springer TA. Overlapping patterns of activation of human endothelial cells by interleukin-1, tumor necrosis factor and immune interferon. J Immunol 1986 137 1893-1896. 

A. H. Stolpen, D. E. Golan, and J. S. Pober, Tumor necrosis factor and immune interferon act in concert to slow the lateral diffusion of proteins and lipids in human endothelial cell membranes, J. Cell Biol. 707 781-789 (1988). 

Other components of the innate response include natural killer (NK) cells and a number of cytokines. NK cells lyse certain types of tumor cells and virally infected cells and are a rich source of immune interferon (interferon-y), which stimulates macrophages and T cells hence they are thought to play an important role in host resistance to both neoplastic and viral disease. Type I interferons (interferon a and interferon P) are produced by a number of different cell types and appear very rapidly after viral infection. Type I interferons inhibit viral replication, inhibit cell proliferation, and increase the lytic potential of NK cells and therefore play a role in controlling viral and neoplastic disease. Several cytokines are important in the initiation of inflammatory responses. Those that have received the most attention include tumor necrosis factor alpha (TNFa), interleukin (IL)-1, and IL-6. There are also a number of chemotactic cytokines (including IL-8), called chemokines, which help to mobilize immune cells to the site of injury. 

Gray, P. W., and Goeddel, D. V. (1983). Cloning and expression of murine immune interferon cDNA. Proc. Natl Acad. Sci. USA 80, 5842 5846. 

The interferon beta-la form (Avonex ) is similarly a immunomodulator used by injection in the treatment of multiple sclerosis. Interferons derived through recombinant DNA technology are labelled (rbe). interferon beta — interferon p. interferon beta-la interferon p. interferon beta-lb interferon p. interferon P2 interleukin 6. interferon yOFN-y MAF immune interferon interferon gamma [ban, inn] formerly called immune interferon Polyferon ) can be isolated from immunologically stimulated T-lymphocytes (hence its former name), and is an IMMUNOMODULAIOR that can be used to treat arthritis and shows activity as an ANTICANCER AGENT. 

STAT proteins have been shown to be critically involved in inflammatory processes of several immune and proliferative disorders [26]. Among them, STAT-1 is activated in response to many lymphocyte-activating cytokines, mainly the interferons, and is essential for cell-mediated immunity. Interferon-y biases the immune system towards a so-called Thl response providing the rationale for the observation that exaggerating Thl responses predominantly underlie chronic inflammatory diseases. 

IFNy, originally described as immune interferon, is synthesized and proteo-lytically processed in activated proliferating T lymphocytes (T19). T lymphocytes were stimulated by a variety of different agents, including IL-2 and virus-... 

Pober, J. S., Collins, T., Gimbrone, M. A., Cotran, R. S., Gitlin, J. D., Fiers, W., Clayberger, C., Krensky, A. M., Burakoff, S. J., and Reiss, C. S. Lymphocytes recognize human vascular endothelial and dermal fibroblast la antigens induced by recombinant immune interferon. Nature (London) 305, 726-729 (1983). 

T19. Trinchieri, G., and Perussia, B. Immune interferon A pleiotropic lymphokine with multiple effects. Immunol. Today 6, 131-136 (1985). 

Goldring, M. B., Sandell, L. J., and Stephenson, M. L. (1986) Immune interferon suppresses levels of procollagen mRN A and type li collagen synthesis in articular and costal chondrocytes. J. Immunol. 261, 9049-9056. 

In cultured DBA/2 mouse peritoneal macrophages pre-treated with supernatants of concanavalin A-stimulated spleen cells containing immune interferon (IFN-y) activity, the acquisition of an intrinsic restriction to herpes simplex virus rephca-tion correlated with the generation of appreciably elevated levels of arginase in supernatant (Sethi 1983),... 

The immune interferon gene has been isolated, sequenced, and expressed.20 One approach for studying the biological activity of immune interferon is to change the amino acid... 

The top part of the figure schematically illustrates the immune interferon gene containing unique restriction endonuclease cleavage site. The remainder of the figure outlines the synthetic strategy as discussed in the text. 

The development of the chemistry outlined in this manuscript was supported by NIH (GM21120 and GM25680) in the author s laboratory. This research was completed by a group of extremely capable and imaginative colleagues whose names appear on the cited references. The synthesis of the immune interferon gene was completed in the laboratories of AMGen Development Inc., Boulder, Colorado, and will be published in detail elsewhere. 

Stabinsky, Y., et al., Total Synthesis of Immune Interferon, in preparation. 

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