The interferons

Interferons were the first family of cytokines to be discovered. In 1957, researchers observed that susceptible animal cells, if they were exposed to a colonizing virus, immediately became resistant to attack by other viruses. This resistance was induced by a substance secreted by virally infected cells which was named interferon. Subsequently, it has been shown that most species actually produce a whole range of interferons. Humans produce at least three distinct classes, IFN-a, IFN-P and IFN-y (Table 8.4). These interferons are produced by a variety of different cell types and exhibit a wide range of biological effects, including:

• induction of cellular resistance to viral attack;

• regulation of most aspects of immune function;

• regulation of growth and differentiation of many cell types;

• sustenance of early phases of pregnancy in some animal species.

No one interferon will display all of these biological activities. Effects are initiated by the binding of the interferon to its specific cell surface receptor present in the plasma membrane of sensitive cells. IFN-a and -P display significant amino acid sequence homology (30 per cent), bind to the same receptor, induce similar biological activities and are acid stable. For these reasons, IFN-a and IFN-P are sometimes collectively referred to as type I interferons, or acid-stable interferons.

Table 8.4 Human interferons and the cells that produce them

Interferon family

Additional name

No. distinct interferons in family

Producing cells

IFN-a

Leukocyte interferon

>15

Lymphocytes

B cell interferon

Monocytes

Lymphoblast interferon

Macrophages

IFN-ß

Fibroblast interferon

1

Fibroblasts

IFN-ß-1a

Some epithelial cells

IFN-y

Immune interferon

1

T-lymphocytes

T cell interferon

NK cells

"Originally a second cytokine was called IFN-P-2, but this was subsequently found to be actually IL-6.

"Originally a second cytokine was called IFN-P-2, but this was subsequently found to be actually IL-6.

IFN-y is evolutionarily distinct from the other interferons; it binds to a separate receptor and induces a different range of biological activities. It is thus often referred to as type II interferon.

Owing to their biological activities most interferons are of actual or likely use in the treatment of many medical conditions, including:

• augmentation of the immune response against infectious agents (viral, bacterial, protozoal, etc.);

• treatment of some autoimmune conditions;

• treatment of certain cancer types.

Interferons may be detected and quantified using various bioassays or by immunoassay systems. Although such assays were available, subsequent purification, characterization and medical utilization of interferons initially proved difficult due to the tiny quantities in which these regulatory proteins are produced naturally by the body. By the early 1970s, advances in animal cell culture technology, along with the identification of cells producing increased concentrations of interferons, made some (mostly IFN-as) available in reasonable quantities. It was not until the advent of genetic engineering, however, that all interferons could be produced in quantities sufficient to satisfy demand for both pure and applied purposes.

8.2.1 The biochemistry of interferon-a

For many years after its initial discovery it was assumed that IFN-a represented a single gene product. It is now known that virtually all species produced multiple, closely related IFN-as. Purification studies from the 1970s on using high-resolution chromatographic techniques (mainly ion-exchange and gel-filtration chromatographies, immunoaffinity chromatography and isoelec-tric focusing) first elucidated this fact.

In humans, at least 24 related genes or pseudo-genes exist that code for the production of at least 16 distinct mature IFN-as. These can be assigned to one of two families, i.e. type I and II. Humans are capable of synthesizing at least 15 type I IFN-as and a single type II IFN-a.

Most mature type I IFN-as contain 166 amino acids (one contains 165), whereas type II IFN-a is composed of 172 amino acids. All are initially synthesized containing an additional 23-amino-acid signal peptide. Based upon amino acid sequence data, the predicted molecular mass of all IFN-as is in the 19-20 kDa range. SDS-PAGE analysis, however, reveals observed molecular masses up to 27 kDa. Isoelectric points determined by isoelectric focusing range between 5 and 6.5. The heterogeneity observed is most likely due to O-linked glycolylation, although several IFN-as are not glycosylated. Some IFN-as also exhibit natural heterogeneity due to limited proteolytic processing at the carboxyl terminus.

Individual IFN-as generally exhibit in excess of 70 per cent amino acid homology with each other. They are rich in leucine and glutamic acid, and display conserved cysteines (usually at positions 1, 29, 99 and 139). These generally form two disulfide bonds in the mature molecule. Their tertiary structures are similar, containing several a helical segments, but appear devoid of P sheets.

Individual members of the IFN-a family each have an identifying name. In most cases the names were assigned by placing a letter after the 'a' (i.e. IFN-aA, IFN-aB, etc.). However, some exceptions exist which contain a number or a number and letter, e.g. IFN-a7, IFN-a8, IFN-a2B. Just to ensure total confusion, several are known by two different names, e.g. IFN-a7 is also known as IFN-aJ1.

8.2.2 Interferon-p

IFN-P, normally produced by fibroblasts, was the first interferon to be purified. Humans synthesize a single IFN-P molecule, containing 166 amino acid residues, that exhibits 30 per cent sequence homology to IFN-as. The mature molecule exhibits a single disulfide bond and is a glycoprotein of molecular mass in excess of 20 kDa. The carbohydrate side chain is attached via an N-linked glycosidic bond to asparagine residue 80. The carbohydrate moiety facilitates partial purification by lectin affinity chromatography. Immunoaffinity chromatography using monoclonal antibodies raised against IFN-P, as well as dye affinity chromatography, has also been employed in its purification. IFN-P's tertiary structure is dominated by five a helical segments, three of which lay parallel to each other, with the remaining two being antiparallel to these.

8.2.3 Interferon-Y

IFN-y is usually referred to as 'immune' interferon. It was initially purified from human peripheral blood lymphocytes. This interferon is produced predominantly by lymphocytes. Its synthesis by these cells is reduced when they come in contact with presented antigen. Additional cytokines, including IL-2 and -12, can also induce IFN-y production under certain circumstances. A single IFN-y gene exists, located on human chromosome number 12. It displays little evolutionary homology to type I interferon genes. The mature polypeptide contains 143 amino acids with a predicted molecular mass of 17 kDa. SDS-PAGE analysis reveals three bands of molecular mass 16-17, 20 and 25 kDa, arising because of differential glycosylation. The 20 kDa band is glycosylated at asparagine 97, whereas the 25 kDa species is glycosylated at asparagines 25 and 97. In addition, mature IFN-y exhibits natural heterogeneity at its carboxyl terminus due to proteolytic-processing (five truncated forms have been identified). The molecule's tertiary structure consists of six a-helical segments linked by non-helical regions.

Gel-filtration analysis reveals bands of molecular mass 40-70 kDa. These represent dimers (and some multimers) of the IFN-y polypeptide. Its biologically active form appears to be a homodimer in which the two subunits are associated in an antiparallel manner.

8.2.4 Interferon signal transduction

All interferons mediate their biological effect by binding to high-affinity cell surface receptors. Binding is followed by initiation of signal transduction, culminating in an altered level of expression of several interferon-responsive genes. Although both positive regulation and negative regulation exist, positive regulation (up-regulation) of gene expression has been studied in greatest detail thus far.

All interferon-stimulated genes are characterized by the presence of an associated interferon-stimulated response element (ISRE). Signal transduction culminates in the binding of specific regulatory factors to the ISRE, which stimulates RNA polymerase II-mediated transcription of the interferon-sensitive genes. The induced gene products then mediate the antiviral, immunomodula-tory and other effects characteristically induced by interferons.

Table 8.5 Cell types which display an IFN-y receptor on their surface

Haematopoietic cells

T-lymphocytes B-lymphocytes Macrophages

Polymorphonuclear leukocytes Platelets

Somatic cells

Endothelial cells Epithelial cells

Various tumour cells

8.2.5 The interferon receptors

The availability of large quantities of purified interferons facilitates detailed study of the interferon receptors. Binding studies using radiolabelled interferons can be undertaken, and photoaffinity cross-linking of labelled interferon to its receptor facilitates subsequent purification of the lig-and-receptor complex. Recombinant DNA technology also facilitated direct cloning of interferon receptors. Binding studies using radiolabelled type I interferons reveals that they all compete for binding to the same receptor, whereas purified IFN-y does not compete. Partial purification of the IFN-a receptor was undertaken by a number of means. One approach entailed covalent attachment of radiolabelled IFN-a to the receptor using bifunctional cross-linking agents, followed by purification of the radioactive complex. An alternative approach utilized an immobilized IFN-a ligand for affinity purification. The receptor has also been cloned, and the gene is housed on human chromosome number 21.

Studies have actually revealed two type I interferon receptor polypeptides. Sequence data from cloning studies place both in the class II cytokine receptor family. Both are transmembrane N-linked glycoproteins. Studies using isolated forms of each show that one polypeptide (called the a/p receptor) is capable of binding all type I interferons. The other one (the ap receptor) is specific for IFN-a-B (a specific member of the IFN-a family). Both receptors are present on most cell types.

The IFN-y receptor (the type II receptor) displays a more limited cellular distribution than that of the type I receptors (Table 8.5). This receptor is a transmembrane glycoprotein of molecular mass 50 kDa, which appears to function as a homodimer. The extracellular IFN-y binding region consists of approximately 200 amino acid residues folded into two homologous domains. Initiation of signal transduction also requires the presence of a second transmembrane glycoprotein known as AF-1 (accessory factor 1), which associates with the extracellular region of the receptor.

The intracellular events triggered upon binding of type I or II interferons to their respective receptors are quite similar. The sequence of events, known as the JAK-STAT pathway, has been elucidated over the last few years. It has quickly become apparent that this pathway plays a prominent role in mediating signal transduction, not only for interferon, but also of many cytokines.

8.2.6 The JAK-STAT pathway

Cytokine receptors can be divided into two groups: those whose intracellular domains exhibit intrinsic protein tyrosine kinase (PTK) activity and those whose intracellular domains are devoid of such activity. Many of the latter group of receptors, however, activate intracellular soluble PTKs upon ligand binding.

Janus kinases (JAKs) represent a recently discovered family of PTKs that seem to play a central role in mediating signal transduction of many cytokines, and probably many non-cytokine regulatory molecules. These enzymes harbour two potential active sites and were thus named after Janus, a Roman god with two faces. It is likely that only one of those 'active' sites is functional. Four members of the JAK family have been best characterized to date: JAK1, JAK2, JAK3 and TYK2. They all exhibit molecular masses in the region of 130 kDa and approximately 40 per cent amino acid sequence homology. They appear to be associated with the cytoplasmic domain of many cytokine receptors, but remain catalytically inactive until binding of the cytokine to the receptor (Figure 8.2).

In most instances ligand binding appears to promote receptor dimerization, bringing their associated JAKs into close proximity (Figure 8.2). The JAKs then phosphorylate (and hence activate) each other (transphosphorylation). The activated kinases subsequently phosphorylate specific tyrosine residues on the receptor itself. This promotes direct association between one or more members of a family of cytoplasmic proteins (signal transducers and activators of transcription (STATs)) and the receptor. Once docked at the receptor surface, the STATs are in turn phospho-rylated (and hence activated) by the JAKs (Figure 8.2). As described below, activated STATs then translocate to the nucleus, and directly regulate expression of interferon and other cytokine-sensitive genes.

As the term STAT suggests, these proteins (a) form an integral part of cytoplasmic signal trans-duction initiated by certain regulatory molecules and (b) activate transcription of specific genes in the nucleus. Thus far, at least six distinct mammalian STATs (STAT1-STAT6) have been identified which range in size from 84 to 113 kDa. Some may be differentially spliced, increasing the number of functional proteins in the family, e.g. STAT1 exists in two forms; STAT1a contains 750 amino acid residues and exhibits a molecular mass of 91 kDa (it is sometimes called STAT91). STAT1P is a splicing variant of the same gene product. It lacks the last 38 amino acid residues at the C-termi-nal of the protein and exhibits a molecular mass of 84 kDa (hence, it is sometimes called STAT84). Similar variants have been identified for STAT3 and STAT5. STATs have also been located in non-mammalian species such as the fruit fly. All STATs exhibit significant sequence homology and are composed of a number of functional domains (Figure 8.3). The SH2 domain functions to bind phosphotyrosine, thus docking the STAT at the activated receptor surface. As detailed below, this domain is also required for STAT interaction with JAKs (which then phosphorylate the STAT) and to promote subsequent dimerization of the STATs. An essential tyrosine is located towards the STAT C-terminus (around residue 700), which in turn is then phosphorylated by PTK.

STATs are differentially distributed in various cells/tissues. STATs 1, 2 and 3 seem to be present in most cell types, all be it at varying concentrations. Tissue distribution of STATs 4 and 5 is more limited.

Not surprisingly different ligands activate different members of the STAT family (Table 8.6). Some, such as STATs 1 and 3, are activated by many ligands, whereas others respond to far fewer ligands, e.g. STAT2 appears to be activated only by type I interferons.

STAT phosphorylation ensures its binding to the receptor, with subsequent disengagement from the receptor in dimeric form. STAT dimerization is believed to involve intermolecular associations between the SH2 domain of one STAT and phosphotyrosine of its partner. Dimerization appears to be an essential prerequisite for DNA binding. Dimers may consist of two identical STATs, but STAT1-STAT2 and STAT1-STAT3 heterodimers are also frequently formed in response to certain cytokines. The STAT dimers then translocate to the nucleus where they bind to specific

Ligand (e.g. a cytokine)

Disassociation (and dimerization) of activatedSTATs, and translocation to nucleus

Disassociation (and dimerization) of activatedSTATs, and translocation to nucleus

CJO QI

Figure 8.2 Simplified overview of the signal transduction process mediated by the JAK-STAT pathway. Refer to text for specific details

Figure 8.2 Simplified overview of the signal transduction process mediated by the JAK-STAT pathway. Refer to text for specific details

Figure 8.3 Schematic representation of the general domain structure of a STAT protein. A conserved ('C' or 'con') domain is located at the N-terminus, followed by the DNA-binding domain (D). Y represents a short sequence that contains the tyrosine residue phosphorylated by the Janus kinase. The carboxy terminus domain (Tr) represents a transcriptional activation domain

Figure 8.3 Schematic representation of the general domain structure of a STAT protein. A conserved ('C' or 'con') domain is located at the N-terminus, followed by the DNA-binding domain (D). Y represents a short sequence that contains the tyrosine residue phosphorylated by the Janus kinase. The carboxy terminus domain (Tr) represents a transcriptional activation domain

Table 8.6 Ligands which, upon binding to their cell surface receptors, are known to promote activation of one or more STATs. (The STATs activated are also shown.) This list, though representative, is not exhaustive

Ligand STAT activated

Table 8.6 Ligands which, upon binding to their cell surface receptors, are known to promote activation of one or more STATs. (The STATs activated are also shown.) This list, though representative, is not exhaustive

Ligand STAT activated

IFN-a

1,

2, 3

IFN-y

1

IL-2

1,

3, 5

IL-3

5

IL-6

1,

3

GM-CSF

5

EGF

1,

3

GH

1,

3, 5

DNA sequences. (STAT2-dependent signalling represents a partial exception. This STAT forms a complex with STAT1 and a non-STAT cytoplasmic protein (p48), and this complex translocates to the nucleus. Binding of this complex to the DNA is believed not to involve STAT2 directly.) STATs bind specific sequences of DNA that approach symmetry, or are palindromic (often TTCC X GGAA, where X can be different bases). These sequences are normally present in upstream regulatory regions of specific genes. Binding of the STAT complex enhances transcription of these genes, and the gene products mediate the observed cellular response to cytokine binding.

A number of proteins that inhibit the JAK-STAT function have also been identified. These include members of the so-called SOCS/Jab/Cis family and the PIAS family of regulatory proteins. Several appear to function by inhibiting the activation of various STATs, although the mechanisms by which this is achieved remain to be elucidated in detail. The JAK-STAT pathway likely does not function in isolation within the cell. JAKs are believed to activate elements of additional signalling pathways, and STATs are also likely activated by factors other than JAKs. As such, there may be considerable crosstalk between various JAK- and/or STAT-dependent signalling pathways.

8.2.7 The interferon JAK-STAT pathway

Binding of type I interferons to the IFN-a/p (type I) receptor results in the phosphorylation and, hence, activation of two members of the JAK family: Tyk2 and JAK1. These kinases then phos-phorylate STATla (also called STAT91), STATip (STAT84) and STAT2 (STAT113). The three activated STATs disengage from the receptor and bind to the cytoplasmic protein p48. This entire complex translocates to the nucleus, where it interacts directly with upstream regulatory regions of interferon-sensitive genes. These nucleotide sequences are termed ISREs. This induces/augments expression of specific genes, as discussed later.

The essential elements of the signal transduction pathway elicited by IFN-y are even more straightforward. IFN-y binding to the type II receptor induces receptor dimerization with consequent activation of JAK1 and JAK2. The JAKs phosphorylate the receptor and subsequently the associated STAT1a. STAT1a is then released and forms a homodimer that translocates to the nucleus. It regulates expression of IFN-y-sensitive genes by binding to a specific upstream regulatory sequence of the gene (the IFN-y activated sequence, GAS). The PIAS-1 protein appears to play an inhibitory role in this pathway. By complexing with (phosphorylated) STAT-1 proteins, it inhibits DNA binding and transactivation.

8.2.8 The biological effects of interferons

Interferons induce a wide range of biological effects. Generally, type I interferons induce similar effects, which are distinct from the effects induced by IFN-y. The most pronounced effect of type I interferons relates to their antiviral activity, as well as their anti-proliferative effect on various cell types, including certain tumour cell types. Anti-tumour effects are likely due not only to a direct anti-proliferative effect on the tumour cells themselves, but also due to the ability of type I interferons to increase NK and T-cytotoxic cell activity. These cells can recognize and destroy cancer cells.

Not all type I interferons induce exactly the same range of responses, and the antiviral to anti-proliferative activity ratio differs from one type I interferon to another. As all bind the same receptor, the molecular basis by which variation in biological activities is achieved is poorly understood as yet.

IFN-y exhibits, at best, weak antiviral and anti-proliferative activity. When co-administered with type I interferons, however, it potentates these IFN-a/p activities. IFN-y is directly involved in regulating most aspects of the immune and inflammatory responses. It promotes activation, growth and differentiation of a wide variety of cell types involved in these physiological processes (Table 8.7).

IFN-y represents the main macrophage-activating factor, thus enhancing macrophage-mediated effects, including:

• destruction of invading microorganisms;

• destruction of intracellular pathogens;

• tumour cell cytotoxicity;

• increased major histocompatibility complex (MHC) antigen expression, leading to enhanced activation of lymphocytes via antigen presentation.

Table 8.7 Cell types participating in the immune, inflammatory or other responses whose activation, growth and differentiation are promoted by IFN-y

Macrophages/monocytes

Polymorphonuclear neutrophils

T-lymphocytes

B-lymphocytes

NK cells

Fibroblasts

Endothelial cells

Binding of IFN-y to its surface receptor on polymorphonuclear neutrophils induces increased expression of the gene coding for a neutrophil cell surface protein capable of binding the Fc portion (i.e. the constant region; see also Box 13.2) of IgG. This greatly increases the phagocytotic and cytotoxic activities of these cells.

IFN-y also directly modulates the immune response by affecting growth, differentiation and function of both T- and B-lymphocytes. These effects are quite complex and are often influenced by additional cytokines. IFN-y acts as a growth factor in an autocrine manner for some T cell sub-populations, and it is capable of suppressing growth of other T cell types. It appears to have an inhibitory effect on development of immature B-lymphocyte populations, but it may support mature B cell survival. It can both up-regulate and down-regulate antibody production under various circumstances.

All interferons promote increased surface expression of class I MHC antigens. Class II MHC antigen expression is stimulated mainly by IFN-y (MHC proteins are found on the surface of various cell types. They play an essential role in triggering an effective immune response against not only foreign antigen, but also altered host cells). Although many interferons promote synergistic effects, some instances are known where two or more interferons can oppose each other's biological activities. IFN-aJ, for example, can inhibit the IFN-aA-mediated stimulation of NK cells.

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2-5' oligoadenylate synthetase (2,5-An synthetase) and the eIF-2a protein kinase.

These intracellular enzymes remain in an inactive state after their initial induction. They are activated only when the cell comes under viral attack, and their activation can inhibit viral replication in that cell. The 2,5-An synthetase acts in concert with two additional enzymes, i.e. an endori-bonuclease and a phosphodiesterase, to promote and regulate the antiviral state (Figure 8.4).

Several active forms of the synthetase seem to be inducible in human cells; 40 kDa and 46 kDa variants have been identified that differ only in their carboxy terminus ends. They are produced as a result of differential splicing of mRNA transcribed from a single gene found on chromosome 11. A larger 85-100 kDa form of the enzyme has been detected, which may represent a heterodimer composed of the 40 and 46 kDa variants.

The synthetase is activated by double-stranded RNA (dsRNA). Although not normally present in human cells, dsRNA is often associated with commencement of replication of certain viruses. The activated enzyme catalyses the synthesis of oligonucleotides of varying length in which the sole base is adenine (2'-5'An). This oligonucleotide differs from oligonucleotides present naturally in the cell, in that the phosphodiester bonds present are 2'-5' bonds (Figure 8.5). The level of synthesis and average polymer length of the oligonucleotide products appear to depend upon the exact inducing interferon type, as well as on the growth state of the cell.

The sole biochemical function of 2'-5'An (and hence 2'-5'An synthetase) appears to be as an activator of a dormant endo-RNase, which is expressed constitutively in the cell. This RNase, known as RNase L or RNase F, cleaves all types of single-stranded RNA (ssRNA). This inhibits production of both viral and cellular proteins, thus paralyzing viral replication. Presumably, cellular destruction of the invading ssRNA will be accompanied by destruction of any additional viral components. Removal of dsRNA would facilitate deactivation of the endo-RNase, allowing translation of cellular mRNA to resume. A 2'-5' phosphodiesterase represents a third enzymatic

Figure 8.4 Outline of how the 2'-5' synthetase system promotes its antiviral effect. The 2'-5' phosphodiesterase 'off switch' is omitted for clarity. Refer to text for details

component of this system. It functions as an off switch, as it rapidly degrades the 2'-5'An oligonucleotides. Although this enzyme also appears to be expressed constitutively, interferon binding appears to increase its expression levels in most cells.

8.2.9 The eIF-2a protein kinase system

Intracellular replication of viral particles depends entirely upon successful intracellular transcription of viral genes with subsequent translation of the viral mRNA. Translation of viral or cellular mRNA is dependent upon ribosome formation. Normally, several constituent molecules interact with each other on the mRNA transcript, forming the smaller ribosomal subunit. Subsequent formation/attachment of the larger subunit facilitates protein synthesis.

Base xJ

Base

Base

Base

Figure 8.5 (a) Structural detail of the 2'-5' oligonucleotides (2'-5'A„) generated by 2'-5'A„ synthetase. Compare the 2'-5' phosphodiester linkages with the 3'-5' linkages characteristic of normal cellular oligonucleotides such as mRNA (b)

5CH2

5CH2

Exposure of cells to interferon normally results in the induction of a protein kinase termed eIF-2a protein kinase. The enzyme, which is synthesized in a catalytically inactive form, is activated by exposure to dsRNA. The activated kinase then phosplorylates its substrate, i.e. eIF-2a, which is the smallest subunit of initiation factor 2 (eIF2). This, in turn, blocks construction of the smaller ribosomal subunit, thereby preventing translation of all viral (and cellular) mRNA (Figure 8.6).

Induction of eIF-2a protein kinase is dependent upon both interferon type and cell type.

IFN-a, -P and -y are all known to induce the enzyme in various animal cells. However, in human epithelial cells the kinase is induced only by type I interferons, whereas none of the interferons seem capable of inducing synthesis of the enzyme in human fibroblasts. The purified kinase is highly selective for initiation factor eIF-2, which it phosphorylates at a specific serine residue.

Interferon, in particular type I interferon, is well adapted to its antiviral function. Upon entry into the body, viral particles are likely to encounter IFN-a/p-producing cells quickly, including macrophages and monocytes. This prompts interferon synthesis and release. These cells act like

IFN binds its receptor, inducing synthesis of eIF-2a protein kinase ^^^

Invading virus

wwwwww.

Cell membrane

Cell cytoplasm cr eIF-2a

eIF-2a (phosphorylated)

Inhibits ribosome formation

Inhibits ribosome formation

Figure 8.6 Outline of how the eIF-2a protein kinase system promotes an antiviral effect sentries, warning other cells of the viral attack. Most body cells express the type I interferon receptor; thus, the released IFN-a or -P will induce an antiviral state in such cells.

The ability of interferons (especially type I interferons) to induce an antiviral state is unlikely to be solely dependent upon the enzymatic mechanisms discussed above. Furthermore the 2'-5'An synthetase and eIF-2a kinase systems may play important roles in mediating additional interferon actions. The ability of such systems to stall protein synthesis in cells may play a role in interferon-induced alterations of cellular differentiation or cell cycle progression. They may also be involved in mediating interferon-induced anti-proliferative effects on various transformed cells.

MHC antigens and P2-macroglobulin are amongst the best known proteins whose synthesis is also induced in a variety of cell types in response to various interferons.

Additional studies focus upon identification and characterization of gene products whose cellular levels are decreased in response to interferon binding. For example, studies using various human and animal cell lines found that IFN-a and -P can induce a significant decrease in the level of c-myc and c-fos mRNA in some cells. IFN-y has also been shown to inhibit collagen synthesis in fibroblasts and chondrocytes. Such studies, elucidating the function of gene products whose cellular levels are altered by interferons, will eventually lead to a more complete picture of how these regulatory molecules induce their characteristic effects.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment