Stem Cells, Vol. 19, No. 5, 467-468,
September 2001
© 2001 AlphaMed Press
FUNDAMENTALS OF CANCER MEDICINE |
The Molecular Perspective: Interferons
David S. Goodsell
David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu www: http://www.scripps.edu/pub/goodsell
Many of the most successful treatments for cancer are simple and direct. Surgery and radiation attack cancer cells in the most physical manner possible. Most chemotherapeutic drugs are similarly direct, attacking weak spots in cancer cells by blocking the action of a key enzyme or stopping the synthesis of a key protein. The action of interferon, however, occurs at a different level than most of the molecules used in chemotherapy. Interferon is not a toxin designed to poison a key molecule in the cell. Instead, it is a message that is read by human cells. Interferon is one of a growing class of cytokines, proteins that deliver instructions from cell to cell. Normally, interferon, and the similar interleukins, mediate a continual conversation between cells about growth and defenses.
Our cells build several different types of interferon (Fig. 1
), for discussing different (but overlapping) topics. The largest group is labeled the alpha-interferons, which are made in one form or another by nearly all cells. These interferons, and the similar beta and omega interferons, are used to mobilize our first line of defense against invading organisms, before the immune system has a chance to get started. When a cell gets a signal from these interferons, it builds specialized proteins to fight an infection. For instance, infected cells construct enzymes that degrade the RNA of growing viruses or they hobble the protein synthesis machinery, slowing the construction of viral proteins. In the process, however, these cells also chop up their own messenger RNA and interfere with their normal protein synthesis, slowing growth to a crawl.
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Figure 1. Interferons. Interferons are relatively small proteins. Alpha-interferon, at the top, is composed of one chain and gamma-interferon, at bottom, is composed of two identical chains. Notice that the two gamma-interferon chains intertwine extensively. Coordinates were taken from entries 1itf and 1rfb at the Protein Data Bank (http://www.pdb.org).
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Gamma-interferon, on the other hand, specializes in a second topic of intercellular conversation. It is made by T-lymphocytes and natural killer cells, delivering messages to other cells in the immune system and telling them to focus on cell-based defenses. Gamma-interferon coaxes cells to build more major histocompatibility complex molecules (Fig. 2) and changes the composition of proteosomes, so that they can display any new anomalous molecules that might be inside. It also activates macrophages and arms them with nitric oxide to help clean up the mess.
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Figure 2. Interferons in action. Interferon initiates a signal that ultimately reaches the nucleus, spurring the synthesis of a collection of specific proteins. The mechanism of gamma-interferon is shown here. Gamma-interferon, shown in red at the top, binds to receptors on the cell surface, shown in yellow. The signal is passed into the cell in a particularly direct way: the single interferon molecule, on the outside of the cell, brings four separate receptor molecules together, so that their interior portions come into contact inside the cell. Several protein tyrosine kinases, fancifully termed Janus kinases (in orange), are bound to these interior portions and when they are brought together, a flurry of mutual phosphorylation ensues. This activates the kinases to perform their ultimate job, which is to add a phosphate to STAT proteins (shown in pink). This activates the STAT proteins and causes them to form dimers. The dimers find their way into the nucleus, shown in the inset at the bottom, and bind to specific regulatory regions of the target genes, starting synthesis.
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As with all aspects of the immune system, the picture is not quite as simple as this tidy description might seem. The messages carried by interferons are complex. Alpha-interferons also modify immune function and gamma-interferon plays a role in defense. Apart from these duties in controlling abnormal growth, they also play supporting roles in the day-to-day maintenance of normal cellular growth levels. The messages are subtle and have different consequences when combined with the many messages passing from cell to cell. This complicates the use of interferon in therapy. Familiar hormones like insulin have simple, direct actions, so insulin is effective in replacement therapy. The artificial messages sent by treatment with interferon, however, can be read incorrectly, leading to unwanted side effects. But in special cases, interferon can send just the right instructions, directing the immune system to destroy hairy cell leukemia cells or inhibiting the growth of blood vessels nourishing a Kaposi's sarcoma.
ADDITIONAL READING
- Bach EA, Aguet M, Schreiber RD. The IFN-gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 1997;15:563-591.
- Johnson HM, Bazer FW, Szente BE et al. How interferons fight disease. Sci Am 1994;269:68-75.
- Stark GR, Kerr IM, Williams BRG et al. How cells respond to interferons. Annu Rev Biochem 1998;67:227-264.
