How much do you know about interferon family

In terms of cytokine drugs, Interferon (IFN) may be familiar to you. At present, interferon is a very popular drug. At first, interferon is used to treat some small diseases such as flu, hepatitis, chickenpox, etc. Now it is used to deal with more complicated diseases, such as cancers and leukemia. And genetically engineered interferons have also been on the market for many years.

Interferon

Let’s take a look at these amazing cytokines:

Interferon (IFN) is a broad-spectrum antiviral agent that does not directly kill or inhibit the virus, but produces antiviral proteins through the action of cell surface receptors, thereby inhibiting the replication of the virus, and at the same time enhancing the vitality of natural killing cells (NK cells), macrophages and T lymphocytes, thereby playing an immunoregulatory role and enhancing antiviral capabilities. Interferon is a group of active proteins (mainly glycoproteins) with multiple functions. It is a cytokine produced by monocytes and lymphocytes. They have a wide range of biological activities such as anti-virus, affecting cell growth, differentiation, and regulating immune function on the same kind of cells. They are currently the most important anti-virus infection and anti-tumor biological products.

Interferon family classification

  1. Type I interferon: Type I interferon includes IFN-αand IFN-β. IFN β is produced by human fibroblasts; IFN-α is mainly produced by monocytes and macrophages; in addition, B cells and fibroblasts can also synthesize IFN-α; IFN-β is mainly produced by fibroblasts. Both IFN-α / β bind to the same receptor and are widely distributed, including monocytes-macrophages, polymorphonuclear leukocytes, B cells, T cells, platelets, epithelial cells, endothelial cells, and tumor cells.
  2. Type II interferon: Type II interferon, gamma interferon, is mainly produced by activated T cells (including Th0, TH1 cells and almost all CD8 + T cells) and NK cells. It is the so-called one type of lymphokine. IFN-γcan exist in the form of extracellular matrix connected, so the cell growth is controlled by a neighboring way, which can be distributed on the surface of almost all cells except mature red blood cells.

In the same type, according to the difference in amino acid sequence, it is divided into several subtypes. It is known that there are more than 23 subtypes of IFN α, which are represented by IFN-α1 and IFN-α2, respectively. There are only one or more subtypes of IFN β and IFN γ, and the physicochemical and biological properties of the three types of interferons are significantly different. Even among the subtypes of IFN α, their biological effects are not the same.

The discovery history

Speaking of the discovery of interferons, it goes back more than 80 years. In 1935, American scientists experimented with monkeys using yellow fever virus. Yellow fever is a malignant disease caused by a virus. There are several types of diseases that people and monkeys can get. They first infected the monkey with a weakly lethal virus. The monkey was safe and sound, and then they infected the same monkey with the highly pathogenic yellow fever virus, but the monkey did not respond. This phenomenon inspired American scientists. They thought the former virus may have produced something that would allow cells to defend themselves when attacked by a new virus. In 1937, a similar experiment was repeated, and it was confirmed that monkeys infected with Rift Valley Fever were injected with yellow fever virus, and the monkeys were fine. Repeated experimental evidence has led scientists to think that viruses in the biological world also have wonderful mutual interference phenomena.

In 1957, British virus biologist Alick Isaacs and Swiss researcher Jean Lindenmann learned that flu-infected cells can produce a factor, which affects other cells and interfere with virus replication, thus it is called interferon.

From 1966 to 1971, Friedman discovered the antiviral mechanism of interferon, which caused people’s attention to the antiviral effect of interferon, and then, the immune regulation of interferon and its antiviral, antiproliferative and antitumor effects were gradually recognized. .

In 1976, Greenberg et al. First reported that 4 cases of chronic active hepatitis B were treated with human interleukin, and 2 cases of HBeAg disappeared after treatment. However, because human leukocyte interferon has limited sources and is expensive, it has not been widely used in clinical practice.

In middle 1970s, the medical community found that patients with chronic hepatitis B have a low ability to produce interferons themselves. After the application of exogenous interferons, the patient not only showed the antiviral effects described above, but also the density of the human leukocyte tissue compatibility on the hepatocyte membrane increased, which  promoted the effectiveness of T cells in lysing infectious hepatocytes. After injection of (2 ~ 5) × 106 units of interferon in adults, the interferon activity in serum began to be measured at 3 hours, reached a high level at 6 hours, and disappeared at 48 hours. After more than ten years, IFN has been used to treat hepatitis B.

In early 1980s, Swiss scientists and American scientists succeeded in developing the first generation of genetically engineered IFN α almost simultaneously. From 1980 to 1982, scientists used genetic engineering methods to obtain interferon in E. coli and yeast cells, and from 20 to 40 milliliters of interferon per liter of cell culture.

In early 1981, Pestka et al. Synthesized and purified IFN α-2a and obtained FDA approval for clinical trials.

In the mid-1980s, after the first genetically engineered IFN α-2a was successfully developed and marketed, it was widely used in clinical practice. The second generation of genetically engineered IFN α-2b was introduced, and its molecular structure is almost the same as human IFN. It was approved by the FDA for the treatment of chronic hepatitis B in 1986. At the same time, Chinese Hou Yunde and other scholars are also studying the preparation of genetic engineering IFN. Since 1987, interferon produced by genetic engineering has entered industrial production and has been put on the market in large quantities.

In 2005, pegylated interferon alpha-2a was approved by the US FDA and officially used for hepatitis B treatment.

Until now, countries using genetic engineering techniques to obtain interferons include the United States, Japan, France, Belgium, Germany, the United Kingdom, and China. A variety of interferons were obtained in large quantities through methods such as DNA recombination and E. coli fermentation. Experiments have shown that the interferon thus prepared has certain effects on viruses such as hepatitis B, rabies, respiratory inflammation, and encephalitis. Interferon can slow the growth of cancer cells, is a promising anti-cancer drug, and has very attractive prospects.

The latest progress

A recent study showed that boosting the body’s production of type I interferon can help clear viral infections. The results were published in the journal Cell.

In this study, the authors found that RIG-I-like receptor (RLR) -mediated production of interferon (IFN) plays a pivotal role in host immunity that enhances virus clearance and cancer immune surveillance. Previous studies have shown that glycolysis is the first step in breaking down glucose to extract cellular metabolic energy, and the authors found that during RLR activation, glycolysis is inhibited, and this inhibitory effect is the key to IFN-I production. Using pharmacological and genetic methods, scientists have shown that reducing lactic acid through inactivation of lactate dehydrogenase A (LDHA) can increase the production of type I IFN, thereby protecting mice from viral infections. The authors say that type I interferon (IFN) plays a vital role in host defenses against viral infections and cancer immune surveillance. In response, the authors plan to conduct additional studies in other animal models to prepare for potential clinical trials.