Interferon

About: Interferon is a research topic. Over the lifetime, 28969 publications have been published within this topic receiving 1219645 citations. The topic is also known as: IFN & interferons.

Antiviral defense in mice lacking both alpha/beta and gamma interferon receptors.

Abstract: Alpha/beta interferon (IFN) and gamma IFN exert widely overlapping biological effects. Still, mice with individually inactivated alpha/beta or gamma receptors exhibit variably severely reduced resistance to infection and altered immune responses. To investigate to what extent the two IFN systems are functionally redundant, we generated mice with a combined receptor defect (AG129 mice). Like mice with individual mutations, AG129 mice had no apparent anomalies, confirming that in the mouse the IFN system is not essential for normal development. These mice showed an additive phenotype with respect to antiviral defense and exhibited an increased susceptibility to lymphocytic choriomeningitis virus (LCMV) and notably vaccinia virus infection. Because of unlimited replication and subsequent rapid exhaustion of cytotoxic T lymphocyte (CTL) precursors, these mice were unable to mount a CTL response to LCMV. CD8(+)-mediated immunopathology was absent in LCMV-infected mice, and virus persisted. Vaccinia virus replicated much faster in AG129 mice, and a 10(4)-fold lower dose of vaccinia virus was sufficient to prime these mice. With the normal priming dose of 10(6) PFU, cytopathic effects and overwhelming infection possibly causing partial exhaustion of CTL interfered with the anti-vaccinia virus response. Even though global antiviral immunoglobulin G (IgG) titers were within normal ranges, the IgG subclass distribution was heavily biased toward IgG1.

Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.

Abstract: Interleukin (IL)-18 induces interferon (IFN)-γ synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rβ2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R–derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin–T cell antigen receptor-αβ transgenic mice (D011.10). Anti–IL-18R antibody inhibited IL-18– induced IFN-γ production by Th1 clones in vitro. In vivo, anti–IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-γ and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Interferon β-1b decreases the migration of T lymphocytes in vitro: Effects on matrix metalloproteinase-9

Abstract: In multiple sclerosis (MS), the influx of activated T lymphocytes into the brain parenchyma leads to the subsequent damage of oligodendrocytes, the cells that produce central nervous system (CNS) myelin. We report here that interferon beta-1b (IFNbeta-1b), a drug shown to be efficacious in the treatment of patients with MS, decreases the in vitro migration of activated T lymphocytes through fibronectin (FN), a major component of the basement membrane that surrounds cerebral endothelium. At 1,000 IU/ml, IFNbeta-1b reduced the migratory rate to that of unactivated T cells. In contrast, IFNgamma at 1,000 IU/ml, which caused a similar decrease (25%) in the proliferation rate of T lymphocytes as IFNbeta-1b, did not affect migration. All T-lymphocyte subsets and natural killer (NK) cells were demonstrated by flow cytometry to be equally affected by IFNbeta-1b treatment. 125I-Western blot analyses revealed that IFNbeta-1b treatment resulted in a marked reduction of the ability of T cells to cleave FN. The substrate-degrading capability of T lymphocytes was shown to be due predominantly to the activity of a 92-kd matrix metalloproteinase, MMP-9, whose levels were decreased by IFNbeta-1b. We suggest that the clinical benefits of IFNbeta-1b treatment in MS patients may be in part a result of the ability of this drug to significantly decrease MMP-9 activity, leading to a reduction of T-lymphocyte infiltration into the CNS.

Synthesis of low molecular weight inhibitor of protein synthesis with enzyme from interferon-treated cells

Abstract: PROTEIN synthesis in cell-free systems from mouse L cells pretreated with the antiviral agent interferon1 shows an enhanced sensitivity to inhibition by double-stranded RNA (dsRNA) (refs 2–4). The inhibition of protein synthesis is dependent on incubation with ATP as well as dsRNA and we and others have reported a dsRNA-dependent protein kinase activity(s) in extracts from interferon-treated cells5–8. The possible involvement of a viral dsRNA-mediated inhibition of protein synthesis in the sequence of events following virus infection in intact, interferon-treated cells has been discussed previously2,4. The situation with extracts from interferon-treated cells5–8 is reminiscent of that in rabbit reticulocyte lysates in which phosphorylation of an initiation factor by a protein kinase has been implicated in the inhibition of protein synthesis in a variety of conditions including the presence of dsRNA9–12. In the interferon-treated L-cell system, however, in addition to the kinase, a heat-stable, low molecular weight inhibitor (LMW inhibitor) of protein synthesis is formed on incubation with ATP and dsRNA (ref. 6). It remained possible from our previous work6, that the LMW inhibitor might be a small phosphorylated peptide product of the dsRNA-dependent kinase. We show here that this is not the case. In addition, we show that the enzyme responsible for the synthesis of the LMW inhibitor will bind to a column of dsRNA attached to a solid support. It can be eluted in high salt but is relatively unstable in this form. We have used the highly-purified enzyme in its stable column-bound state to synthesise and radioactively label the LMW inhibitor. This synthesis, the partial purification of the inhibitor and its activity in the inhibition of protein synthesis in cell-free systems from L cells and rabbit reticulocytes, are reported here. A more detailed characterisation of the inhibitor is described in the accompanying paper13.