Interferon-gamma (
IFN-γ) is a
dimerA dimer is a chemical or biological entity consisting of two structurally similar subunits called monomers, which are joined by bonds, which can be strong or weak.- Organic chemistry :...
ized soluble
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
that is the only member of the type II class of
interferonInterferons are natural cell-signaling proteins produced by the cells of the immune system of most vertebrates in response to challenges such as viruses, parasites and tumor cells. They belong to the large class of glycoproteins known as cytokines and are produced by a wide variety of cells in...
s. 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 geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
.
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.
Interferon-gamma (
IFN-γ) is a
dimerA dimer is a chemical or biological entity consisting of two structurally similar subunits called monomers, which are joined by bonds, which can be strong or weak.- Organic chemistry :...
ized soluble
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
that is the only member of the type II class of
interferonInterferons are natural cell-signaling proteins produced by the cells of the immune system of most vertebrates in response to challenges such as viruses, parasites and tumor cells. They belong to the large class of glycoproteins known as cytokines and are produced by a wide variety of cells in...
s. 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 geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
.
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, but, most important, derives from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer (
NKNatural killer cells are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses...
) and natural killer T (
NKTNatural killer T cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self- and foreign lipids and glycolipids...
) cells as part of the innate immune response, and by
CD4CD4 is a glycoprotein expressed on the surface of T helper cells, regulatory T cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
and
CD8CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
cytotoxic T lymphocyte (
CTLA cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or dysfunctional...
) effector T cells once
antigenAn antigen is a substance that prompts the generation of antibodies and can cause an immune response. "Self" antigens are usually tolerated by the immune system; whereas "Non-self" antigens are identified as intruders and attacked by the immune system...
-specific immunity develops.
Structure
The IFN-γ
monomerA monomer is a small molecule that may become chemically bonded to other monomers to form a polymer...
consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region. 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 1Interferon gamma receptor 1 also known as CD119 , is a human gene.- Function :...
(IFNGR1) and
Interferon gamma receptor 2Interferon gamma receptor 2 also known as IFNGR2 is a protein which in humans is encoded by the IFNGR2 gene.- Function :This gene encodes the non-ligand-binding beta chain of the gamma interferon receptor...
(IFNGR2). IFN-γ binding to the receptor activates the JAK-STAT pathway. IFN-γ also binds to the
glycosaminoglycanGlycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit.-Production:...
heparan sulfateHeparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
(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.
The structural models shown in figures 1-3 for IFN-γ are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids in length, the models are 126 amino acids in length. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids. 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. In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form. 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.
Biological activity
In contrast to
interferon-αHuman type I interferons comprise a vast and growing group of IFN proteins.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor that consists of IFNAR1 and IFNAR2 chains....
and
interferon-βHuman type I interferons comprise a vast and growing group of IFN proteins.All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor that consists of IFNAR1 and IFNAR2 chains....
, which can be expressed by all cells, IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells. Also known as immune interferon, IFN-γ is the only Type II
interferonInterferons are natural cell-signaling proteins produced by the cells of the immune system of most vertebrates in response to challenges such as viruses, parasites and tumor cells. They belong to the large class of glycoproteins known as cytokines and are produced by a wide variety of cells in...
. It is
serologicallySerology is the scientific study of blood serum. In practice, the term usually refers to the diagnostic identification of antibodies in the serum...
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. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Amongst the effects are:
- Increase antigen presentation of macrophage
Macrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...
s.
- Activate and increase lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s:
[[nucleolus]]
[[cell nucleus|nucleus]]
[[ribosomes]]
[[vesicle |vesicle]]
...
activity in macrophages
- Suppress Th2 cell activity.
- Cause normal cells to increase expression of class I MHC molecules
- Promotes adhesion and binding required for leukocyte migration
- Promotes NK cell activity
- Activates APCs and promotes Th1 differentiation by upregulating the transcription factor
In the field of molecular biology, a transcription factor is a protein that binds to specific DNA sequences and thereby controls the transfer of genetic information from DNA to mRNA...
T-betT-box transcription factor TBX21 is a protein that in humans is encoded by the TBX21 gene....
.
IFN-γ is the hallmark
cytokineCytokines are any of a number of substances that are secreted by specific cells of the immune system which carry signals locally between cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins,...
of Th1 cells (whereas Th2 cells produce IL-4 and
Th17 cellT helper 17 cells are a newly discovered subset of T helper cells producing interleukin 17. They are considered developmentally distinct from Th1 and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease such as Multiple Sclerosis...
s produce
IL-17Interleukin-17 is the founding member of a group of cytokines called the IL-17 family. IL-17A, was originally identified as a transcript from a rodent T-cell hybridoma by Rouvier et al. in 1993...
). NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses
osteoclastAn osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption...
formation by rapidly degrading the
RANKRANK , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. RANK is also expressed on dendritic cells and facilitates immune signaling...
adaptor protein
TRAF6TRAF6 is a TRAF human protein.-Interactions:TRAF6 has been shown to interact with SDCBP, IRAK2, IRAK1, MAP3K7IP2, MAP3K7IP1, TNFRSF13B, FHL2, CD40, IKBKG, RANK, HSPB2, UBE2N, SIGIRR, TAX1BP1, ASK1, PPP4C, TNFAIP3, Sequestosome 1, MAP3K7 and Ubiquitin C....
in the
RANKRANK , also known as TRANCE Receptor, is a type I membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. RANK is also expressed on dendritic cells and facilitates immune signaling...
-
RANKLRANKL , also known as TNF-related activation-induced cytokine , osteoprotegerin ligand , and ODF , is a molecule important in bone metabolism. This natural and necessary surface-bound molecule activates osteoclasts, cells involved in bone resorption...
signaling pathway, which otherwise stimulates the production of NFκB.
Therapeutic use
Interferon gamma 1b is used to treat
chronic granulomatous diseaseChronic granulomatous disease is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens...
and
osteopetrosisOsteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to the more prevalent osteomalacia, in which the bones soften.It can cause...
.
Interactions
Interferon-gamma has been shown to
interactProtein-protein interactions involve not only the direct-contact association of protein molecules but also longer range interactions through the electrolyte, aqueous solution medium surrounding neighbor hydrated proteins over distances from less than one nanometer to distances of several tens of...
with
Interferon gamma receptor 1Interferon gamma receptor 1 also known as CD119 , is a human gene.- Function :...
.
Further reading