Research reportIs interferon-α a neuromodulator?
Introduction
Interferons (IFNs) were originally detected in immunological cells and have been shown to be produced during non-immunological responses of both central and peripheral origins. Interferons' biological properties include antiviral activity as an inhibitor of viral proliferation and enhancement to immune function [80]. Subsequently they were shown to have diverse biological activities, including antitumor activity [69]and biological response modifier activities [23]. Furthermore, it is established that a variety of stimuli act on different cells to give rise to various types of IFNs. Three types of IFNs are known; α, β and γ. They are a family of proteins that appear in a large variety of vertebrates, from fish to homo sapiens and comprised of a complex endogenous proteins, glycoproteins, and peptides 9, 23, 26, 80, 100, 123. Initially, interferon-α (IFN-α) was thought to be produced by macrophages, leukocytes, and monocytes. In vivo, IFN-α is produced at a constant low `physiological' level 24, 25, 27, 121, 173. The focus of this review is on IFN-α, since this cytokine exerts most active influence on the nervous system.
Immunologic therapy uses cytokines such as IFN to treat various hematologic malignancies and infectious ailments as well as autoimmune diseases such as multiple sclerosis 8, 9, 26, 111. Multiple sclerosis (MS) is a chronic disease of the nervous system and experimental autoimmune encephalomyelitis (EAE) is an animal model resembling MS. In both cases, there is a deficiency of natural killer (NK) cells, which is correlated with disease severity. Interferon-α administration in mice and rats inhibits EAE inducers 1, 2and protects mice from EAE and death [161]. In vitro NK activity can be normalized with IFN-α treatment 86, 101, 170, while in MS patients the treatment reduces relapses and stabilizes disease progression for prolonged periods 8, 81, 82, 111. Many infections and neuroinflammatory diseases are associated with acute and chronic pain states [172]. Interestingly, clinical treatment using IFN-α or IFN-γ in cancer patients has lead to sensory abnormalities including pain 132, 160, while spinally applied IFN-γ facilitates the flexor reflex in spinalized rats. This may represent an analogue of behavioral hyperalgesia [172].
Each type of the IFN is usually administered daily or every other day by injection, but long-term treatment is needed for the therapy to be effective. Because the cytokines used in immunologic therapy are naturally produced in the body, they were thought to be non-toxic [72]. Moreover, several adverse effects are reported to be frequent in long-term IFN-α therapies. Besides the activation of immunity, IFN-α produces a broad spectrum of non-immunologic host defenses in the counterreply to infection. These include sensory and motor disturbance, fever, anorexia, confusion, depression and sleep, which are considered central nervous system (CNS) dysfunction symptoms 102, 108, 122, 124, 125, 127, 135, 149, 153.
The above features indicate that IFN-α affects CNS processes. Although the effects of IFN-α have been extensively studied in a variety of systems, the IFN-α role has not been studied in the nervous system and warrants further explanation. Until the early 1980's, only a few laboratories 18, 32using behavioral and electrophysiological procedures, had investigated whether IFN-α affects CNS activity.
Section snippets
Interferon receptors and interferon binding in the CNS
The brain is relatively isolated from the immune system due to the presence of the blood brain barrier (BBB), which limits the penetration of circulating lymphocytes and antibodies [51]. Small amounts of IFNs have been reported to penetrate the deep layers of the brain after intrathecal administration 102, 168and after systemic application in the cerebrospinal fluid 35, 74. It is thought that systemically administered IFN-α enters the brain through areas lacking the BBB. Significant
Behavioral modification by IFN-α
Interferon therapy is usually administered daily or every other day by injection and long-term administration is needed for the therapy to be effective [70]. This causes dose characteristic CNS side effects, which are reversed by stopping the IFN treatments 4, 79, 106, 107. Following `low' dose IFN-α treatment in cancer patients, the most debilitating side effects are fatigue, asthenia, anorexia, influenza-like symptoms of fever, chills, headaches, myalgia, somnolence and lethargy 4, 36, 68, 79
Interferon-α and the endocrine system
Previous studies indicate that the action of IFN-α requires binding to specific receptors of the cell surface 6, 7. This binding may share sites common to those of peptide hormones such as ACTH 18, 19, 20and TSH [91]. The detection of ACTH and endorphin-like substances from lymphocytes infected with newcastle disease virus (NDV) was the first demonstration that the immune system is capable of producing peptides capable of signaling the neuroendocrine system. The cells of the immune system
Interferon-α and opiates
The effects of opiate peptides on the secretion of IFNs and other cytokines has generally been described as stimulatory and bimodal [140]. According to Brown and Van Epps [29], β-endorphin and Met-enkephalin increase IFN-γ production, while Lysle et al. [99]reported that morphine suppresses release of IFN-γ. Similarities have been demonstrated among the structures of proopiomelanocortin, β-endorphin and IFN-α that link IFN-α with opiates. Other evidence linking IFN-α with opiates is provided by
Interferon-α modulates fever and thermosensitive neurons
It is now established that fever is a host defense response to various exogenous pathogenic organisms or their products, such as lipopolysaccharides, and that it is mediated centrally by endogenous pyrogens which include IFN-α [21]. Fever is thought to be initiated as a result of the activation of thermosensitive neurons located mainly in the preoptic/anterior hypothalamus (PO/AH) area by yet unknown mechanisms. When injected intravenously (i.v.) or i.c.v. in rabbits, cats and mice, IFN-α
Interferon-α modulates the peripheral nervous system
Compartments of the immune system, such as the spleen, are innervated by the noradrenergic sympathetic nerve originating in the hypothalamus 10, 67. An i.c.v. injection of IFN-α elicits an increase in the activity of splenic sympathetic activity, which results in suppression of splenic natural killer (NK) cell activity 77, 87, 88, 163, 165. Splenic denervation has been reported to completely abolish the immunosuppressive effect of IFN-α 10, 165. This suggests that the sympathetic nerve
Interferon-α modulates electroencephalogram (EEG) activity
Multiple IFN-α therapy elicits several CNS side effects, indicating that this therapy affects the sensory, motor, hypothalamus and limbic systems as well as the thalamus, and the reticular formation 5, 33, 78, 102, 124, 127, 135, 149, 153. Based on these reports, permanent electrodes were implanted in the rat motor and sensory cortices for EEG recording and in several subcortical motor, sensory and limbic brain sites for EEG-like recording, as well as in the caudate nucleus, which is a
Interferon-α modulates evoked field potentials
Single injections of IFN-α in unanesthetized freely behaving rats, implanted previously with permanent electrodes, results in the potentiation of the sensory evoked potential recorded from the sensory cortex and VMH as compared with the control recording [45]. However, the same treatment in the same animal resulted in attenuating the sensory evoked responses recorded from the preoptic/anterior hypothalamus (PO/AH) area and no response from the medial thalamus (Fig. 3). Thus, in some areas of
Interferon-α modulates single neuron activity
Gresser's group were the first to report the effect of IFN-α on single neuronal activity [32]. They reported that IFN-α enhances the spontaneous activity of neurons in cerebral and cerebellar cat cortices as well as rat nerve cell cultures. Changes in these firing rates occurred after about 30 min and the excitation lasted for several hours. When repetitive stimulation was applied and the responses before and after IFN-α treatment were compared, marked shortening of the latency to the initial
Interferon-α modulate food intake and glucose sensitive neurons
One of the side effects elicited by IFN-α therapy is anorexia resulting in loss of more than 15% of the patient's body weight 5, 108, 141, 153. A similar decrease in food intake following IFN-α treatment was found in animals 36, 124, 126, 137, 143, 150. Appetite regulation is a profoundly complex process. The major CNS sites participating in control of food intake are thought to be the lateral hypothalamus (LH), the PVN and the VMH 43, 44, 148, 166. It has been suggested that the VMH is `a
Conclusion
Interferons were discovered as natural antiviral substances produced during viral infection. However, more recently, results indicate that the property of IFN-α to hinder viral replication is only one of its functions, and that IFN-α is involved in many physiological systems.
(1) Interferon-α crosses the BBB, is both produced and secreted in the brain, and binds to brain tissue at specific binding sites.
(2) Interferon-α treatment elicits dose characteristic behavioral CNS effects such as lack of
Acknowledgements
I would like to thank Drs Larry Laufman and Stanley Board as well as Ms Diana Parker for manuscript preparation.
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