Interferon-gamma

Interferon-gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons.^[2] This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs. In humans, the IFN-γ protein is encoded by the IFNG gene.^[3][4]

Function

IFN-γ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. Aberrant IFN-γ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops.^[4][5]

Structure

The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.^[6][1] This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6.

The biologically active dimer is formed by anti-parallel inter-locking of the two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue.

Receptor binding

Cellular responses to IFN-γ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFN-γ binding to the receptor activates the JAK-STAT pathway. IFN-γ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFN-γ to HS inhibits its biological activity.^[7]

The structural models shown in figures 1-3 for IFN-γ^[1] are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids long, the models are 126 amino acids long. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids.^[8] Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters.^[9] In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form.^[7] Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming.

The biological significance of heparan sulfates interaction with IFN-γ is unclear, however binding of the D1 cluster to HS may protect it from proteolytic cleavage.^[9]

Biological activity

In contrast to interferon-α and interferon-β, which can be expressed by all cells, IFN-γ is secreted by T helper cells (specifically, T_h1 cells), cytotoxic T cells (T_C cells) and NK cells. Also known as immune interferon, IFN-γ is the only Type II interferon. It is serologically distinct from Type I interferons and it is acid-labile, while the type I variants are acid-stable.

IFN-γ has antiviral, immunoregulatory, and anti-tumor properties.^[10] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:

• Promotes NK cell activity
• Increase antigen presentation and lysosome activity of macrophages.
• Activate inducible Nitric Oxide Synthase iNOS
• Promotes T_h1 differentiation by upregulating the transcription factor T-bet, ultimately leading to cellular immunity: cytotoxic CD8+ T-cells and macrophage activity - while suppressing Th2 differentiation which would cause a humoral (antibody) response
• Cause normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen presenting cells—specifically through induction of antigen processing genes, including subunits of the immunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself
• Promotes adhesion and binding required for leukocyte migration
• Induces the expression of intrinsic defense factors—for example with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects

IFN-γ is the primary cytokine which defines T_h1 cells: T_h1 cells secrete IFN-γ, which in turn causes more undifferentiated CD4⁺ cells (Th0 cells) to differentiate into T_h1 cells, representing a positive feedback loop—while suppressing T_h2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for T_h2 cells and IL-17 for Th17 cells.)

NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of NF-κB.

Activity in Granuloma Formation

A granuloma is the bodies way of dealing with a substance it cannot remove or sterilize. Infectious causes of granulomas (infections are typically the most common cause of granulomas) include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis and cat scratch disease. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, giant-cell arteritis, Wegener's granulomatosis, Churg-Strauss syndrome, pulmonary rheumatoid nodules and aspiration of food and other particulate material into the lung. The infectious pathophysiology of granulomas is discussed primarily here.

The key association between interferon-γ and granulomas is that interferon-γ activates macrophages so that they become more powerful in killing intracellular organisms. Activation of macrophages by T_h1 helper cell's hallmark cytokine interferon-γ in mycobacterial infections, allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages). So the first step is the activation of T_h1 helper cells by macrophages releasing IL-1 and IL-12 in the presence of intracellular pathogens, as well as the presentation of some of antigens in MHC class II surface protein. Next the T_h1 helper cells aggregate around the macrophages and release interferon-γ which causes the activation of macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, further presentation of antigens to Th1 helper cells with further release of interferon-γ. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells further walling off the infection.

Therapeutic use

Interferon-γ 1b is used to treat chronic granulomatous disease^[11] and osteopetrosis.^[12] It is manufactured by InterMune as Actimmune(TM) and costs around USD300 per vial.

Interactions

Interferon-γ has been shown to interact with Interferon gamma receptor 1.^[13][14]

Regulation

There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR.^[15] There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-29.^[16]

References

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.