Biological and clinical basis for molecular studies of interferons

Abstract

The cytokine family of interferons (IFNs) has multiple functions, including antiviral, anti-tumor, and immunomodulatory effects and regulation of cell differentiation. The multiple functions of the IFN system are thought to be an innate defense against microbes and foreign substances. The IFN system consists first of cells that produce IFNs in response to viral infection or other foreign stimuli and second of cells that establish the antiviral state in response to IFNs. This process of innate immunity involves multiple signaling mechanisms and activation of various host genes. Viruses have evolved to develop mechanisms that circumvent this system. IFNs have also been used clinically in the treatment of viral diseases. Improved treatments will be possible with better understanding of the IFN system and its interactions with viral factors. In addition, IFNs have direct and indirect effects on tumor cell proliferation, effector leukocytes and on apoptosis and have been used in the treatment of some cancers. Improved knowledge of how IFNs affect tumors and the mechanism that lead to a lack of response to IFNs would help the development of better IFN treatments for malignancies.

Fig. 1.

Overview of the cellular events in the induction, production, and action of IFN foreign substances (1) induce a variety of cell types; (2) to produce and secrete IFN (3). The secreted IFN (α, β, or γ) acts directly on target cells (4) and also acts indirectly against target cells by activating effector lymphocytes or macrophages (5).

Fig. 2.

Overview of the molecular events in the induction, production, and action of IFN. Inducers of IFN react with cells to newly induce the messenger RNA (mRNA) for interferon, which is translated into the interferon protein, which is then secreted extracellularly. The extracellular interferon binds to the IFN receptors on the membrane of surrounding (or the producing) cells to initiate a JAK/STAT signaling cascade. Those signals activate the IFN-response genes to produce mRNA for the IFN-effector proteins. The effector proteins mediate the antiviral, anti-tumor, immunomodulatory, and all differentiation effects of the IFN system as described in the text.

Fig. 3.

The roles of innate and adaptive immunity during acute influenza virus infection of humans. During virus infection, the earliest defenses are innate. They include interferon, anatomic barriers, nonspecific inhibitors, phagocytosis, fever, and inflammation. The innate defenses begin within hours and continue until virus is eliminated. The adaptive defenses are specific antibody and cell-mediated immunity. They begin within 5 to 7 d of infection and persist for months after virus is eliminated. Virus levels initially increase rapidly, begin to decline in the presence of the innate defenses, and virus is eliminated after the development of the adaptive defenses. Adapted from ref. .

Fig. 4.

Effect of 100 g of poly I:CLC given intramuscularly on virus multiplication in mouse organs after intraperitoneal infection with vaccinia virus strain Ihd