Interferon-a receptor

One possibility is an additional covalent modification, such as phosphorylation of serine 727 of STAT 1, which occurs only in response to INF-y. Dephosphorylation may also contribute to the specificity of INF signalling, because the tyrosine phosphatase, FTP ID, which is associated with IFNARl (the interferon-a receptor 1) participates in the response to INF-cc/p. ... 

The class II cytokine receptor family includes receptors for interferon a/P (lEN a/P) and y (lENy) and IL-10. lEN-y immunoreactivity has been found in neurons in the hypothalamus, cerebral cortex, mammilary nuclei, and dorsal tegmentum. Astrocytes and microglia in vitro can be stimulated to express class II histocompatibiHty complex (MHC-II) antigens by lEN-y, which may be involved in the presentation of antigen to T-ceUs by astrocytes. Thus lEN-y may be critical in CNS-immune function and dysfunction especially in regard to neuronal and gHal apoptotic processes. 

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Gentz, R., Hayes, A., Grau, N. et al. (1992) Analysis of soluble human and mouse interferon-gamma receptors expressed in eukaryotic cells. European Journal of Biochemistry, 210 (2), 545-554. 

Li, J. and Roberts, M. 1994. Interferon-T and interferon-a interact with the same receptors in bovine endometrium. Journal of Biological Chemistry 269(18), 13 544-13 550. 

Since cellular immunity results in the release of chemotactic lymphocytes that in turn enhance phagocytosis, a deficiency in cellular immunity may also result in chronic infections. Cellular immunity is mediated by T cells, macrophages, and NK cells involved in complex compensatory networks and secondary changes. Immunosuppressive agents may act directly by lethality to T cells, or indirectly by blocking mitosis, lymphokine synthesis, lymphokine release, or membrane receptors to lymphokines. In addition, cellular immunity is involved in the production and release of interferon, a lymphokine that ultimately results in blockage of viral replication (Table 15.4). Viruses are particularly susceptible to cytolysis by T cells since they often attach to the surface of infected cells. Thus, immunosuppression of any of the components of cellular immunity may result in an increase in protozoan, fungal, and viral infections as well as opportunistic bacterial infections. 

Jouanguy, E., Lanhamedi-Cherradi, S., Altare, E, etal, Partial interferon-y receptor I deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J. Clin. Invest. 100, 2658-2664 (1997). 

Many cytokines exhibit redundancy, i.e. two or more cytokines can induce a similar biological effect. Examples include TNF-a and -P, both of which bind to the same receptor and induce very similar if not identical biological responses. This is also true of the interferon-a family of proteins and interferon-/ , all of which bind the same receptor. 

Interferon a, P, y INF-Ra, INF-RP, INF-Ry, receptors with associated tyrosine kinase... 

At least four types of cytokine receptors can be differentiated on the basis of sequence homology (Fig. 11.2). Many members of the cytokine receptors of type 1 regulate growth and transmit mitogenic signals to the cell nucleus. The cytokine receptors of type 2 include the receptors for the interferons a and p. Type 3 includes the receptors for tiunor necrosis factor TNF and for CD 40 and Fas protein, which are foimd on T lymphocytes. 

Fig. 11.8. Scheme of signal transduction via interferon a. The receptor for interferon a (IFNa) binds and activates the Jak kinases Jakl and Tykl. These phosphorylate the Stat factors Statl and Stat2, leading to formation of Statl-Stat2 heterodimers. The heterodimers are transported into the nucleus and bind to a corresponding DNA element known as ISRE (interferon stimulated response element). Another protein, p48, is also involved in transcription activation of the interferon regulated gene. 

Igarashi , Garotta G, Ozmen L, Ziemiecki A, Wilks AF, Harpur AG, Lamer AC, Finbloom DS. Interferon gamma induces tyrosine phosphorylation of interferon gamma receptor and regulated association of protein tyrosine kinases, Jakl and Jak2, with its receptor. J Biol Chem 1994 269 14333-14336. 

Sakatsume M, Igarashi K-I, Winestock KD, Garotta G, Larner AC, Finbloom DS. The Jak Kinases differentially associate with the a and b (accessory factor) chains of the interferon-g receptor to form a functional receptor unit capable of activating ST AT transcription factors. J Biol Chem 1995 270 17528-17534. 

Ozmen L, Roman D, Fountoualakis M, Schmid G, Ryffel B, Garotta G. Soluble interferon-gamma receptor a therapeutically useful drug for systemic lupus erythematosus. J Interferon Res 1994 14(5) 283-284. 

Dessein, A.J., Hillaire, D., Elwali, N.E., Marquet, S., Mohamed-Ali, Q., Mirghani, A., Henri, S., Abdelhameed, A.A., Saeed, O.K., Magzoub, M.M. and Abel, L. (1 999) Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. American journal of Human Genetics 65, 709-721. 

Wilson, R.A., Coulson, P.S., Betts, C., Dowling, M.A. and Smythies, L.E. (1996) Impaired immunity and altered pulmonary responses in mice with a disrupted interferon-gamma receptor gene exposed to the irradiated Schistosoma mansoni vaccine. Immunology 87, 275-282. 

Huang, S., Hendriks, W., Althage, A., Hemmi, S., Bluethmann, H., Kamijo, R., Vilcek, J., Zinkernagel, R. M., and Aguet, M. (1993). Immune response in mice that lack the interferon-gamma receptor. Science 259, 1742-1745. 

Lundell, D., Lunn, C. A., Senior, M. M., Zavodny, P. J., and Narula, S. K. (1994). Importance of the loop connecting A and B helices of human interferon-gamma in recognition by interferon-gamma receptor./. Biol. Chem. 269, 16159-16162. 

Pernis, A., Gupta, S., Gollob, K. J., Garfein, E., Coffman, R. L., Schindler, C., and Rothman, P. (1995). Lack of interferon gamma receptor beta chain and the prevention of interferon gamma signaling in THl cells. Science 269, 245-247. 

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