Review article
Interferon and the central nervous system

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Abstract

Interferons (IFNs) were discovered as natural antiviral substances produced during viral infection and were initially characterized for their ability to “interfere” with viral replication, slow cell proliferation, and profound alteration of immunity. The IFNs are synthesized and secreted by monocytes, macrophages, T-lymphocytes, neurons, and glia cells. The different IFNs are classified into three classes: alpha, beta, and gamma. α-IFN produced in the brain exerts direct effects on the brain and endocrine system by activating the neurosecretory hypothalamic neurons and regulates the hypothalamic–pituitary–adrenocortical axis. IFNs modulate neurophysiological activities of many brain region involving in pain, temperature, and food intake regulation. α-IFN administration activates the sympathetic nerves innervating components of the immune system. IFNs may serve as regulatory mediators between the central nervous system, the immune system, and endocrine system. IFN is used as immunologic therapy to treat various hematologic malignancies and infectious ailments and autoimmune diseases.

Introduction

Interferons (IFNs) are a family of naturally occurring complex proteins, glycoproteins and peptides that are synthesized and released by many vertebrates from fish to Homo sapiens. IFNs are produced in vivo by macrophages, monocytes, T lymphocytes, glia, and neurons (Larsson et al., 1978, Maruo, 1988, Plata-Salaman, 1991) at a constant “physiological” level. They act as intracellular messengers by altering the function of many different kinds of cells to induce and maintain physiological functions (Isaacs and Lindenmann, 1957, Marcovitz et al., 1984, Pestka et al., 1987, Baron et al., 1991, Bocci, 1988a, Bocci, 1988b, Bocci, 1992). IFNs induce cell adhesion molecules that play an important role in development (Maroun, 1995), modulate cellular metabolism, and control growth and differentiation (Campbell et al., 1999). They also exert “cellular” effects such as antiproliferative effects on cells (Paucker et al., 1962), enhance the expression of immunologically relevant cell membrane constituents, and activate natural killer cells and macrophages, as well as possess anti-tumor effects (Isaacs and Lindenmann, 1957, Kirchner, 1984, Pestka et al., 1987, Baron et al., 1991, Bocci, 1988a, Bocci, 1992). In addition, IFNs have high biological activity since cells of every species, from lower vertebrates to man, produce their own IFNs.

Interferons were discovered by Isaacs and Lindenmann (1957) in their antiviral experiments aiming to produce antiviral compound and to interfere with viral multiplication. They infected egg membranes with live viruses and discovered that the viruses failed to grow. They concluded that some forms of viral interference resulted from their treatment. They isolated the protein and named it “interferon” (IFN) since it interfered with viral growth. Interferons released into the bloodstream and intracellular fluid induce the production of an enzyme that counters the viral infection by preventing the viruses from replicating in the body (Bocci, 1992). Interferons bind to specific receptors on the cell surface and elicit a variety of cellular responses. The different IFNs were initially classified as leukocyte IFN, fibroblast IFN, and immune IFN according to their supposed production by a particular cell and organ site. Later, IFNs were classified into three different types on the basis of antigenicities of their proteins and biological properties: α-, β- and γ-IFNs (Bocci, 1985, Bocci, 1988a, Bocci, 1988b, Bocci et al., 1985, Paulesu et al., 1985, Yasuda, 1993, Makino et al., 2000).

α-IFN is a protein with immunomodulatory, antiproliferative and antiviral properties. α-IFN plays a critical role in maintaining the balance of the immune system by stimulating natural killer cells. It is used in the treatment of hairy cell leukemia, AIDS-related kaposis, sarcoma, genital warts, and chronic hepatitis B and C. Exogenous α-IFN initially has been produced by infection of white blood cells in cultures (Kirchner, 1984, Pestka, 2000).

β-IFN is an immunoregulatory cytokine. It inhibits certain white blood cells, and is used mainly in the treatment of multiple sclerosis (MS), autoimmune neurites, and chronic inflammation demyelinating polyradiculoneuropathy (Creange et al., 1998, Hadden et al., 1999, Zou et al., 1999, Schaller et al., 2001, Pritchard et al., 2003, Vallat et al., 2003). β-IFN slows the growth of disease fighting white blood cells by stopping their production of myelin-destroying compound as well as correcting the deficiency of T cells that control the immune system. β-IFN is an important antiviral cytokine (Carr et al., 2003) because it stimulates the production of natural killer cells. In vivo, β-IFN is produced by fibroblasts that are stimulated by viruses or synthetic inducers (Pestka, 2000). α-IFN and β-IFN are also produced in response to viral infections to control herpes simplex virus type I (HSV-1) replication (Carr et al., 2003). Since β-IFN shares about 60% homology with α-IFN and since α-IFN and β-IFN exhibit many additional similarities, they are combined into one group known as type I IFNs.

γ-IFN was discovered several years after the discovery of α-IFN as an antiviral activity in the supernatant of human lymphocytes stimulated with mitogen. γ-IFN was the first lymphokine with its molecular structure identified. Lymphokines are defined as a substance produced by lymphocytes upon the activation of macrophages and act on the cellular components of the immune system such as T lymphocytes and thus lymphokines are immunoregulatory molecules (Kirchner, 1984). γ-IFN is a representative of two groups of biological important molecules, the lymphokines and the IFNs (Kirchner, 1984). γ-IFN is not structurally related to α-IFN or β-IFN (Adolf, 1985, Kubota et al., 2001). The γ-IFN is a macrophage activating protein that modulates a variety of biological pathways potentially relevant to muscle wasting and immune dysfunction. γ-IFN is predominantly produced by T lymphocytes and natural killer cells. It is also produced by astrocytes and microglial cells in the central nervous system (CNS) (De Simone et al., 1998, Xiao and Link, 1998, Kubota et al., 2001). γ-IFN regulates the immune system and responds to infectious agent by helping the body to fight infection and tumors (Gray and Goeddel, 1982, Kaur et al., 2003). It is used mainly to treat chronic granulomatous disease and osteopetrosis. γ-IFN is an activator of macrophages and natural killer cells; thus, it increases their anti-tumor activities, as well as regulates B cells immune responses and increases the secretion of the immunoglobins.

Due to the presence of the blood brain barrier, the brain is relatively isolated from the other organ systems, limiting the penetration of circulating lymphocytes and antibody to the brain (Darling et al., 1981). However, small amounts of IFNs have been reported to penetrate the brain (Cathala and Baron, 1970, Habif et al., 1975, Mattson et al., 1983, Vass and Lassmann, 1990). There is some evidence that IFNs enter the brain through areas lacking the blood brain barrier. Indeed, significant concentration of IFNs is found on sites such as the hypothalamus and pons, where the blood brain barrier is more permeable (Zimmerman and Krivoy, 1973, Scott et al., 1981, Bocci, 1985, Bocci, 1992, Smith et al., 1985, Smith et al., 1986, Wiranowska et al., 1989). Since IFNs used in immunologic therapy are synthesized and released naturally in the body, they were thought to be nontoxic (Goldstein and Laszlo, 1988). However, several adverse effects were reported as a result of exogenous IFN treatment, such as insomnia, sensory and motor abnormality, fever, anorexia, flu-like symptoms, malaise, muscle pain (myalgia), depression, paraesthesia, amnesia, anxiety, dementia with apathy, cognitive dysfunction, confusion and depression (Scott et al., 1981). Wichers and Maes (2002) suggested that γ-IFN, α-IFN, and other cytokines induced side effects as a result of alteration of serotonin, noradrenergic, and hypothalamic–pituitary–adrenal systems. All of these symptoms are CNS mediated phenomena (Cantell et al., 1980, Mattson et al., 1983, Smedley et al., 1983, Ackerman et al., 1994, Iivanainen et al., 1985, Hori et al., 1991, Valentine et al., 1998, Schaefer et al., 1999). Therefore, this review will focus on the role of IFN on CNS activity.

Section snippets

Interferon classes and receptors

In general, the IFN family is divided into two groups — type I and type II IFNs. Type I IFNs consist of four major classes: α-IFN, β-IFN, ω-IFN, and τ-IFN, while γ-IFN belongs to type II IFNs (Pestka et al., 1987, Baron et al., 1991, Campbell et al., 1999, Pestka, 2000, Soos and Szente, 2003). The type I α-IFN and β-IFN (α/β-IFN) are comprised of the products of multiple α-IFN genes and a single β-IFN gene (Biron, 2001). Type I IFNs share a common receptor and exhibit similar biological

The central nervous system, the immune system and interferon

Reciprocal interactions between the CNS and immune system have gain new significance with the establishment of putative pathways of intercommunication between the CNS and immune system. This interaction occurs essentially at two levels: 1) cell to cell contact and 2) release of soluble mediators that bind to cell surface receptors (Hood et al., 1984, Cooper et al., 1986). Several morphological and physiological substrates were identified to provide the circuitry for reciprocal communication

The endocrine system and interferon

Stimulation of the immune system resulted in the production and release of several cytokines and hormones (Smith and Blalock, 1981, Hood et al., 1984, Smith et al., 1985, Smith et al., 1986, Späth-Schwalbe et al., 1989, Walters et al., 1998, Besedovsky and Del Rey, 2002). It was reported that leukocyte IFN provides an afferent link between the immune and the endocrine systems (Blalock and Smith, 1980, McCain et al., 1982). This conclusion was based on the detection of ACTH and endorphin-like

Drowsiness, sleep and interferon

Cytokines such as IFN treatment are somnogenic and are involved in the sleep–wake regulation (Shoham et al., 1987, Krueger and Majde, 1995, Spath-Schwalbe et al., 2000, Cadinali and Esquifino, 2003). Most living organisms exhibit behavioral and physiological rhythms with a cycle of about 24 h that is regulated by an internal time-keeping system called the circadian clock, which acts like a multifunctional timer in regulating the homeostatic system, such as sleep and wakefulness (Koyanagi and

Anorexia, food intake and interferon

The brain areas that regulate and control food intake are thought to be the ventromedial hypothalamus, lateral hypothalamus, and paraventricular hypothalamic area (Dafny and Jacobson, 1975, Tempel et al., 1993, Oomura, 1988, Dafny et al., 2004). The lateral hypothalamus is considered as “a center involved in initiating feeding” (Schanzer et al., 1978, Morley, 1987) or “a feeding center” involved in initiating food intake (Oomura, 1988, Reyes-Vazquez et al., 1994, Dafny et al., 2004). The

Fever, temperature and interferon

Regulation of core temperature is essential since most of the metabolic processes necessary for life are temperature-dependent. The preoptic/anterior hypothalamus area contains three types of neurons sensitive to cold, heat, and different degrees of temperature. These neurons are involved in determining the temperature set-point. Therefore, the preoptic/anterior hypothalamus area is suggested as the site of temperature regulation (Ackerman et al., 1994, Dinarello et al., 1984).

Fever is a host's

Hypothalamic glucose sensitive neurons and interferons

Interferon treatment suppresses food intake in humans and animals (Mattson et al., 1983, Bocci et al., 1985, Hori et al., 1991, Meyers and Valentine, 1995). Food intake provides nutrients to support the continuous energy demands that contribute to caloric homeostasis as well as maintains a stable body weight. Two major hypotheses have been put forth to account for feeding and the process by which the usual balance in caloric intake is established: 1) the depletion–repletion hypothesis and 2)

Opiate and interferon

Morphine treatment inhibits the secretion and reduces the level of circulating endogenous α-IFN (Gober et al., 1975, Hung et al., 1973), as well as decreases the capability of cells to produce α-IFN (Vilcek et al., 1968). The degree of α-IFN reduction was dose-dependent, i.e., with increased morphine dose, more decrease in α-IFN circulating level was observed (Hung et al., 1973). Moreover, α-IFN shares some pharmacological properties similar to β-endorphin, such as the production of analgesia

Clinical use of IFN

Administration of IFN has a wide range of efficacy in hematological malignancies, including tumors of presumed B cell, T cell, and myeloid lineages, kaposis sarcoma, lymphoma, polycythemia vera, chronic myelogenous leukemia, hairy cell leukemia, virus infection, hepatitis C, hepatitis B, and multiple sclerosis (Dafny et al., 2004). Multiple sclerosis is an autoimmune disease. It occurs when the body's immune system attacks the body's own myelin. Damage to the myelin compromises the CNS

Conclusion

Cytokines are synthesized and secreted in physiological levels by macrophages, leukocytes, monocyte, T lymphocytes, glia, and neurons as well as in response to viral infection. Subsequently, they are known to be diverse biological response modifiers and participate in many physiological activities and as inhibitor of viral proliferation, anti-tumor activity and enhancement to immune functions. This review focuses on one family of cytokines, the IFNs, and summarizes reports showing that there

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