Interferons

Interferons are species-specific proteins that induce antiviral and antiproliferative responses in animal cells. They are a major defense against viral infections and abnormal growths (neoplasms). Interferons are produced in response to penetration of animal cells by viral (or synthetic) nucleic acid and then leave the infected cell to confer resistance on other cells of the organism .

Interferons are a group of proteins known primarily for their role in inhibiting viral infections and in stimulating the entire immune system to fight disease . Research has also shown that these proteins play numerous roles in regulating many kinds of cell functions. They can promote or hinder the ability of some cells to differentiate, that is, to become specialized in their function. They can inhibit cell division , which is one reason why they hold promise for stopping cancer growth. Recent studies have also found that one interferon may play an important role in the early biological processes of pregnancy. Although once thought to be a potential cure-all for a number of viral diseases and cancers, subsequent research has shown that interferons are much more limited in their potential. Still, several interferon proteins have been approved as therapies for diseases like chronic hepatitis , genital warts, multiple sclerosis, and several cancers.

The first interferon was discovered in 1957 by Alick Isaacs and Jean Lindenmann. During their investigation, the two scientists found that virus-infected cells secrete a special protein that causes both infected and noninfected cells to produce other proteins that prevent viruses from replicating. They named the protein interferon because it "interferes" with infection . Initially, scientists thought there was only one interferon protein, but subsequent research showed that there are many different interferon proteins.

Types of interferons and how they work

Interferons are members of a larger class of proteins called cytokines (proteins that carry signals between cells). Most interferons are classified as alpha, beta, or gamma interferons, depending on their molecular structure. Two other classes of interferons—omega and tau—have also been discovered. So far, more than 20 different kinds of interferon-alpha have been discovered but only beta and one gamma interferon have been identified.

Interferons are differentiated primarily through their amino acid sequence. (Amino acids are molecular chains that make up proteins.) Interferon-alpha, -beta, -tau, and -omega, which have relatively similar amino acid sequences, are classified as type I interferons. Type I interferons are known primarily for their ability to make cells resistant to viral infections. Interferongamma is the only type II interferon, classified as such because of its unique amino acid sequence. This interferon is known for its ability to regulate overall immune system functioning.

In addition to their structural makeup, type I and type II interferons have other differences. Type I interferons are produced by almost every cell in the body while the type II interferon-gamma is produced only by specialized cells in the immune system known as T lymphocytes and natural killer cells. The two classes also bind to different kinds of receptors, which lie on the surface of cells and attract and combine with specific molecules of various substances.

Interferons work to stop a disease when they are released into the blood stream and then bind to cell receptors. After binding, they are drawn inside the cell's cytoplasm, where they cause a series of reactions that produce other proteins that fight off disease. Scientists have identified over 30 disease fighting proteins produced by interferons.

In contrast to antibodies, interferons are not virus specific but host specific. Thus, viral infections of human cells are inhibited only by human interferon. The human genome contains 14 nonallelic and 9 allelic genes of alpha-interferon (macrophage interferon), as well as a single gene for beta-interferon (fibroblast interferon). Genes for any two or more variants of interferon, which have originated from the same wild-type gene are called allelic genes and will occupy the same chromosomal location (locus ). Variants originating from different standard genes are termed non allelic. Alpha- and beta-interferons are structurally related glycoproteins of 166 and 169 amino acid residues. In contrast, gamma-interferon (also known as immune interferon) is not closely related to the other two and is not induced by virus infection. It is produced by T cells after stimulation with the cytokine interleukin-2. It enhances the cytotoxic activity of T cells, macrophages and natural killer cells and thus has antiproliferative effects. It also increases the production of antibodies in response to antigens administered simultaneously with alpha-interferon, possible by enhancing the antigen-presenting function of macrophages.

Interferons bind to specific receptors on the cell surface, and induce a signal in the cell interior. Two induction mechanisms have been elucidated. One mechanism involves the induction of protein kinase by interferon, which, in the presence of double-stranded RNA, phosphorylates one subunit of an initiation factor of protein synthesis (eIF-2B), causing the factor to be inactivated by sequestration in a complex. The second mechanism involves the induction of the enzyme 2',5'-oligoadenylate synthetase (2',5'-oligo A synthestase). In the presence of double-stranded RNA, this enzyme catalyses the polymerisation of ATP into oligomers of 2 to 15 adenosine monophosphate residues which are linked by phosphodiester bonds between the position 2' of one ribose and 5' of the next. These 2',5'-oligoadenylates activate an interferon specific RNAase, a latent endonuclease known as RNAase L which is always present but not normally active. RNAase cleaves both viral and cellular single stranded mRNA. Interferons therefore do not directly protect cells against viral infection, but rather render cells less suitable as an environment for viral replication. This condition is known as the antiviral state.

Interferons and the immune system

In addition to altering a cell's ability to fight off viruses, interferons also control the activities of a number of specialized cells within the immune system. For example, type I interferons can either inhibit or induce the production of B lymphocytes (white blood cells that make antibodies for fighting disease). Interferon-gamma can also stimulate the production of a class of T lymphocytes known as suppressor CD8 cells, which can inhibit B cells from making antibodies.

Another role of interferon-gamma is to increase immune system functioning by helping macrophages, still another kind of white blood cell, to function. These scavenger cells attack infected cells and also stimulate other cells within the immune system. Interferon-gamma is especially effective in switching on macrophages to kill tumor cells and cells that have been infected by viruses, bacteria , and parasites .

Interferon-tau, first discovered for its role in helping pregnancy to progress in cows, sheep , and goats , also has antiviral qualities. It has been shown to block tumor cell division and may interfere with the replication of the acquired immune deficiency, or AIDS , virus. Since it has fewer unwanted side-effects (flu-like symptoms and decreased blood cell production) than the other interferons, interferon-tau is becoming a new focal point for research.

Interferon's medical applications

In 1986, interferon-alpha became the first interferon to be approved by the Food and Drug Administration (FDA) as a viable therapy, in this case, for hairy-cell leukemia . (Interferons are used therapeutically by injecting them into the blood stream.) In 1988, this class of interferons was also approved for the treatment of genital warts, proving effective in nearly 70% of patients who do not respond to standard therapies. In that same year, it was approved for treatment of Kaposi's sarcoma, a form of cancer that appears frequently in patients suffering from AIDS. In 1991, interferon-alpha was approved for use in chronic hepatitis C, a contagious disease for which there was no reliable therapy. Interferon has been shown to eliminate the disease's symptoms and, perhaps, prevent relapse. Interferon-alpha is also used to treat Hodgkin's lymphoma and malignant melanoma, or skin cancer.

In 1993, another class of interferon, interferon-gamma, received FDA approval for the treatment of a form of multiple sclerosis characterized by the intermittent appearance and disappearance of symptoms. It has also been used to treat chronic granulomatous diseases, an inherited immune disorder in which white blood cells fail to kill bacterial infections, thus causing severe infections in the skin, liver, lungs, and bone. Interferon-gamma may also have therapeutic value in the treatment of leishmaniasis, a parasitic infection that is prevalent in parts of Africa , America, Europe , and Asia .

Although all of the disease fighting attributes of interferon demonstrated in the laboratory have not been attained in practice, continued research into interferons will continue to expand their medical applications. For example, all three major classes of interferons are under investigation for treating a variety of cancers. Also, biotechnological advances making genetic engineering easier and faster are making protein drugs like interferons more available for study and use. Using recombinant DNA technology, or gene splicing , genes that code for ineterferons are identified, cloned, and used for experimental studies and in making therapeutic quantities of protein. These modern DNA manipulation techniques have made possible the use of cell-signaling molecules like interferons as medicines. Earlier, available quantities of these molecules were too minute for practical use.

Another particular area of interest is the use of inter-ferons to enhance other therapies. For example, studies have shown that a combination of interferon-alpha and tamoxifen may be a more effective therapy for breast cancer than either used alone. Future studies will focus more on combining interferons with other drug therapies.

See also Antibody and antigen; Immunology.

Resources

books

Janeway, Charles A., et al. Immunobiology. 5th ed. New York and London: Garland Publishing, 2001.

periodicals

Johnson, Howard M., Fuller W. Bazer, Brian E. Szente, and Michael A. Jarpe. "How Interferons Fight Disease." Scientific American (May 1994): 68–76.

Meulen, Volkerter, and Stefan Niewiesk. "Inhibition of Major Histocompatibility Complex Class II-Dependant Antigen Presentation by Nutralization of Gamma Interferon Leads to Breakdown of Resistance against Measles Virus-Induced Encephalitis." Journal of Virology 75 (2000):1–13.

Seppa, Nathan. "Interferon Delays Multiple Sclerosis." ScienceNews 158 (November 2000): 280–281.

other

Multiple Sclerosis Society. Interferons. [cited April 3, 2003] <http://www.interferons.com>.

Worman, M.D., J. Howard. "Interferon Treatment of Viral He patitis". Dept. of Gastrointestinal Diseases, Columbia University. April 6, 2002 [January 2003]. <http://cpmcnet.coumbia.edu/dept/gi/intron.html>.

David Petechuk Judyth Sassoon

KEY TERMS

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Immune system

—That network of tissues and cells throughout the body which is responsible for ridding the body of invaders such as viruses, bacteria, protozoa, etc.

Proteins

—Macromolecules made up of long sequences of amino acids. They make up the dry weight of most cells and are involved in structures, hormones, and enzymes in muscle contraction, immunological response, and many other essential life functions.

Type I interferons

—A group of interferons that have similar amino acid sequences. They include the alpha, beta, tau, and omega interferons.

Type II interferons

—A type of interferon that has a unique amino acid sequence. Interferon gamma is the only interferon in this group.