Interferon-gamma (IFN-gamma) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-gamma ligand, receptor, signal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-gamma signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-gamma are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-alpha, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0603252

Interferon-γ: an overview of signals, mechanisms and functions

Molecular profile of reactive astrocytes—Implications for their role in neurologic disease

The last ten years have seen an explosive growth in our understanding of IFN gamma. The cloning of the cDNAs for IFN gamma and its receptor have made available large amounts of highly purified recombinant IFN gamma and soluble IFN gamma receptor. In addition, highly specific neutralizing monoclonal antibodies have been generated to both of these proteins. Using these reagents, IFN gamma and the IFN gamma receptor have been characterized on a molecular basis. Structure-function studies carried out on these proteins have identified key molecular regions that are required for biologic activity. Moreover, a great deal is now known concerning the physiologic role that IFN gamma plays in vivo. In this review we focus on the new developments in the areas of IFN gamma biochemistry and biology and pay particular attention to the IFN gamma receptor and three aspects of IFN gamma biology that are of special interest to immunologists: host defense, inflammation, and autoimmunity.

/pdf/the-molecular-cell-biology-of-interferon-gamma-and-its-3by8w0vlph.pdf

The Molecular Cell Biology of Interferon-gamma and its Receptor

For over 35 years, immunologists have divided T-helper (TH) cells into functional subsets. T-helper type 1 (TH1) cells—long thought to mediate tissue damage—might be involved in the initiation of damage, but they do not sustain or play a decisive role in many commonly studied models of autoimmunity, allergy and microbial immunity. A major role for the cytokine interleukin-17 (IL-17) has now been described in various models of immune-mediated tissue injury, including organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and the nervous system. A pathway named TH17 is now credited for causing and sustaining tissue damage in these diverse situations. The TH1 pathway antagonizes the TH17 pathway in an intricate fashion. The evolution of our understanding of the TH17 pathway illuminates a shift in immunologists' perspectives regarding the basis of tissue damage, where for over 20 years the role of TH1 cells was considered paramount.

http://cnc.cj.uc.pt/BEB/private/pdfs/2007-2008/Immunology/A/Rev_paper_A5.pdf

A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.

Numerous innate and adaptive immune effector cells and molecules participate in the recognition and destruction of cancer cells, a process that is known as cancer immunosurveillance. But cancer cells avoid such immunosurveillance through the outgrowth of poorly immunogenic tumour-cell variants (immunoselection) and through subversion of the immune system (immunosubversion). At the early stages of carcinogenesis, cell-intrinsic barriers to tumour development seem to be associated with stimulation of an active antitumour immune response, whereas overt tumour development seems to correlate with changes in the immunogenic properties of tumour cells. The permanent success of treatments for cancer might depend on using immunogenic chemotherapy to re-establish antitumour immune responses.

/pdf/cancer-despite-immunosurveillance-immunoselection-and-3zwc1svpt3.pdf

Cancer despite immunosurveillance: immunoselection and immunosubversion

Acute experimental allergic encephalomyelitis (EAE) was induced in C57BL/6J and SJL/J mice by injection of isologous spinal cord homogenate given in conjunction with Bordetella pertussis and Freund's adjuvant. SJL/J mice showed a highly aggressive and 100% lethal form of the disease; C57BL/6J mice were much less susceptible as they had low morbidity rates (20 to 40%), low disease scores, and mostly no mortality. Treatment of these low susceptibility mice with neutralizing mAb against IFN-gamma caused an increase in morbidity rates as well as significant mortality (up to 80%). Similar antibody treatment did not affect the course of the disease in the high susceptibility SJL/J mice. However, treatment of these mice with IFN-gamma resulted in reduced morbidity and mortality. A similar but less pronounced inhibition of the disease in SJL/J mice could be obtained by administration of IFN-alpha/beta or by acute infection with lactate dehydrogenase virus. The results indicate that endogenous as well as exogenous IFN can exert a down-regulating effect on the development of EAE. They also indicate that endogenous IFN-gamma is produced during the development of EAE and plays a disease-limiting role.

Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma.

Footpad swelling developing in mice after local injection of LPS (S marcescens) was found to consist of two phases with peaks occurring on days 2 to 3 and 6 to 8, respectively Histopathologically, the reaction was characterized by edema and mononuclear cell infiltration; the second peak was associated with intravascular thrombosis as is typically described for the Shwartzman reaction to LPS Recombinant DNA-derived IFN-gamma, administered by ip injection, had a suppressive effect on the development of the reaction The same effect was seen with recombinant DNA-derived IFN-alpha 1 and with the natural mixture of IFN-alpha and -beta In mice pretreated with neutralizing monoclonal antibodies to IFN-gamma, the footpad response to LPS was modified in that a delayed monophasic rather than a biphasic response occurred These data indicate that LPS induces local production of IFN-gamma, which acts as a trigger or positive regulator of the reaction The effect of a single pretreatment with neutralizing anti-IFN-gamma antibody was found to last for as long as 6 wk Experiments in which antibody administration was delayed till after LPS challenge indicated that endogenous IFN-gamma was also involved in the late phases of the inflammation The results show that regulation of inflammation by interferons is complex in that local IFN-gamma acts as a positive factor, whereas systemic IFN-alpha 1 and -gamma, probably through indirect mechanisms, downregulate inflammation

Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide.

Exogenous plasmid isolation was used to assess the presence of mobilizing plasmids in several soils and activated sludges. Triparental matings were performed with Escherichia coli (a member of the gamma subgroup of the Proteobacteria) as the donor of an IncQ plasmid (pMOL155, containing the heavy metal resistance genes czc: Co, Zn, and Cd), Alcaligenes eutrophus (a member of the beta subgroup of the Proteobacteria) as the recipient, and indigenous microorganisms from soil and sludge samples as helper strains. We developed an assay to assess the plasmid mobilization potential of a soil ecosystem on the basis of the number of transconjugants obtained after exogenous isolations. After inoculation into soil of several concentrations of a helper strain (E. coli CM120 harboring IncP [IncP1] mobilizing plasmid RP4), the log numbers of transconjugants obtained from exogenous isolations with different soil samples were a linear function of the log numbers of helper strain CM120(RP4) present in the soils. Four soils were analyzed for the presence of mobilizing elements, and mobilizing plasmids were isolated from two of these soils. Several sludge samples from different wastewater treatment plants yielded much higher numbers of transconjugants than the soil samples, indicating that higher numbers of mobilizing strains were present. The mobilizing plasmids isolated from Gent-O sludge and one plasmid isolated from Eislingen soil hybridized to the repP probe, whereas the plasmids isolated from Essen soil did not hybridize to a large number of rep probes (repFIC, repHI1, repH12, repL/M, repN, repP, repT, repU, repW, repX). This indicates that in Essen soil, broad-host-range mobilizing plasmids belonging to other incompatibility groups may be present.

Exogenous isolation of mobilizing plasmids from polluted soils and sludges.

Methodology for selection of best available techniques (BAT) at the sector level

Monitoring of microbial DNA in soils by dot blot hybridization and PCR analysis is a useful technique for gaining insight into the survival and impact of genetically modified micro-organisms released in the environment. Most methods of DNA isolation from soils require a large number of purification steps rendering them unsuitable for quantitative analysis of multiple samples. Here we describe a very rapid method for the isolation and purification of multiple samples of soil DNA that can be used directly for dot blot hybridization and PCR analysis. Soil DNA extracts are prepared by lysozyme/SDS treatment at pH 9.0 and purified by ammonium acetate precipitation and Sephadex G50 gel filtration. In a practical application of this method, sandy soil samples were seeded with Alcaligenes eutrophus cells and exposed to high temperature (42 degrees C) or desiccation. As a result, the number of culturable A. eutrophus cells which could be recovered from the soil samples quickly declined. However, the concentration of a marker gene encoding resistance to cadmium, cobalt and zinc (czc) remained unaltered.

R Dijkmans

Papers

Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma.

Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide.

Exogenous isolation of mobilizing plasmids from polluted soils and sludges.

Methodology for selection of best available techniques (BAT) at the sector level

Rapid method for purification of soil DNA for hybridization and PCR analysis.