Interferon inhibition

Urban, J.F., Madden, K.B., Cheever, A.W., Trotta, P.P., Katona, I.M. and Finkelman, F.D. (1993) Interferon inhibits inflammatory responses and protective immunity in mice infected with the nematode parasite, Nippostrongylus brasiliensis. Journal of Immunology 151, 7086-7094. 

Although interferon has been studied extensively for over a decade, the mechanism of its antiviral activity remains unclear. Considerable evidence exists to support the concept that interferon inhibits virus-specific protein synthesis, thus blocking viral replication in cells adjacent to the infected cell producing the interferon. There is no established reason to conclude, however, that interferon exerts antiviral action through a single mechanism. 

Sobel DO, Ahvazi B. Alpha-interferon inhibits the development of diabetes in NOD mice. Diabetes 1998 47 1867-72. 

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. 

Grosser, I., Aguet, M., Morel-Maroger, L., Woodrow, D., Puvion-Dutilleul, F., Guillon, J. C., and Maury, C. (1981). Elec-trophoretically pure mouse interferon inhibits growth, induces liver and kidney lesions, and kills suckling mice. Am. J. Pathol. 102, 396 2. 

Adverse reactions are common and include an influenza-like syndrome (naturally-produced interferon may cause symptoms in natural influenza infection), fatigue and depression which respond to lowering the dose. Other effects are emorexia (sufficient to induce weight loss), convulsions, hypotension, hypertension, cardiac arrhythmias and bone marrow depression. Interferons inhibit the metabolism of theophylline, increasing its effect. 

Interferons (IFN) are glycoproteins which possess antiviral, antiproliferative and immunomodulatory properties. Besides the main types a, P and y, other forms are available (lymphoblastoid IFNa, consensus IFNa). Administration is subcutaneous. Bioavailability is about 90%. The serum peak is reached by using IFNa2a after 6-8 hours with a half-life period of 5 hours or by using IFNa2b after 3-12 hours with a half-life of 3 hours. Elimination is primarily via the kidneys. Interferons inhibit CYPIA2. There is no development of resistance. (158, 160, 182) (see chapter 40.5.1.1)... 

Taklmoto, M., Ohkoshi, S., Ichida, T., Takeda, Y., Nomoto, M., Asa-knra. A., Naito, A., Mori, S., Hata, K., Igarashi, K., Hara, H., Ohta, H., Soga, K., Watanabe, T., Kamimura, T. Interferon inhibits progression of liver fibrosis and reduces the risk of hepatocarcinogenesis in patients with chronic hepatitis C. A retrospective multicenter analysis of 652 patients. Dig. Dis. Sci. 2002 47 170-176... 

The so-called resistant strains, however, show a different response to mercury exposure. These resistant strains also show an increase in MHC expression molecules on B-cells, but this response is extremely short-lived, and increases in serum IgE were not observed (Dubey et al. 1991a Prouvost-Danon et al. 1981). The difference in the responses of the so-called resistant and susceptible strains may be found in the activation of Thl cells and the increase in secretion of -interferon by the Thl cells of resistant animals (van der Meide et al. 1993). The susceptible strains do not show an increase in -interferon production with mercury exposure. Because -interferon inhibits the proliferation of Th2 cells, the absence of this response in the susceptible strains may allow the Th2 cell-stimulated production of autoantibodies to occur, whereas in the resistant strains the production of antibodies is curtailed. Thus, differences in the activation of Thl versus Th2 cells may underlie the differences in susceptibility of various individuals. Studies using in-bred strains of mice and rats have determined that the susceptibility to the different immune reactions is governed by both MHC genes as well as other genes (Aten et al. 

Taldmoto M, Ohkoshi S, Ichida T, Takeda Y, Nomoto M, Asakura H, et al. Interferon inhibits progression of liver fibrosis and reduces the risk of hepatocarcino-genesis in patients with chronic hepatitis C A retrospective multicenter analysis of 652 patients. Dig Dis Sci 2002 47 170-6. 

Ito M, Natsume A, Takeuchi H, Shimato S, Ohno M, Wakabayashi T, Yoshida J (2009) Type I interferon inhibits astrocytic gliosis and promotes functional recovery after spinal cord injury by deactivation of the MEK/ERK Pathway. J Neurotrauma 26 41-53... 

Gribaudo G, Ravaglia S, Caliendo A, Cavallo R, Gariglio M, Martinotti MG, Landolfo S (1993) Interferons inhibit onset of murine cytomegalovirus immediate-early gene transcription. Virology 197 303-311... 

The induction of apoptosis in virus-infected cells is an important defense mechanism of the host. Apoptosis of a virus-infected cell occurs either as a direct response to viral infection or on recognition of infection by the host immune system. Viruses have evolved different strategies to evade host immune responses including inhibition of antibody- and complement-mediated effects, interference with interferons, inhibition and modulation of cytokines and chemokines, blockade of antigen presentation, and also inhibition of apoptosis (Spriggs 1996 Alcami and Koszinowski 2000). 

Metz DH, Esteban M. Interferon inhibits viral protein synthesis in L-cells infected with vaccinia virus. Nature 1972 238(5364) 385-388. 

Lotan R, Dawson MI, Zou CC, Jong L, Lotan D, Zou CP (1995) Enhanced efficacy of combinations of retinoic acid and retinoid X receptor-selective retinoids and a-interferon inhibition of cervical carcioma cell proliferation. Cancer Res 55 232-236... 

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