Interleukin-1 in the Brain

Nancy J. Rothwell

• Publisher: Pergamon
• Year: 2013
• Print ISBN: 9780080419961
• eBook ISBN: 9781483287768
• Topic: Biological Sciences
• Subtopic: Physiology
• Index: Biological Sciences

Interest in interleukin-1 (IL-1) has increased dramatically over the last decade, but has been largely restricted to immunologists, cell biologists and those studying inflammation and cancer. However, it has recently been recognized that the brain directly controls or modulates many aspects of immune function, while molecules classically associated with the immune system, such as interleukin-1, are synthesised within the brain and act directly on the central nervous system to modify local and systemic functions. Thus, this topic is relatively new to neurobiologists, and this book is the first comprehensive description of current knowledge on interleukin-1 in the brain, including its location, synthesis and receptors, actions on behaviour, fever, metabolism, neuroendocrine function, electrical activity of the brain, nerve growth factor, and relationship to clinical indications. The book is organised into three sections. The first reviews the data available on the neural localisation of IL-1 and the nature of its central receptors. The main part of the book examines the different neural effects of IL-1 and the mechanisms which are involved in these actions, comparing IL-1 where possible to other inflammatory cytokines which also have neurotrophic effects. The final section evaluates the possible role of IL-1 in neural plasticity and neuronal degeneration.

1

Location of interleukin-1 in the nervous system

MARIANNE SCHULTZBERG, Clinical Research Center, Division of Medical Cell and Neurobiology, Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden

Publisher Summary

An important activity related to interleukin-1 (IL-1) is its proliferative effects, especially in the nervous system. This chapter discusses the morphological data on the occurrence of IL-1 in the peripheral and central nervous system with special reference to the role of IL-1 in the hypothalamo-pituitary-adrenocortical axis and as a neuronal growth factor. One of the original actions of EL-1 that lead to its characterization is the pyrogenic effect. Electrophysiological studies have demonstrated that IL-1 stimulates neurons in the anterior hypothalamus where the temperature set point is regulated. Hence, the peripheral administration of a well-defined protein may directly or indirectly affect temperature set point centres in the brain. In an in vitro system based on mouse spinal cord and dorsal root ganglion cells, it was observed that addition of antibodies to IL-1α resulted in an increase in nerve cell degeneration, and this effect was blocked by IL-1α. Also, the addition of vasoactive intestinal polypeptide (VIP) blocked the neurodegenerative effects of IL-1 antibodies.

The interrelationship between the nervous and immune systems has, in recent years, attracted considerable attention and been the subject of an increasing number of studies. In order to begin to understand the morphological and molecular basis for this interaction, we initiated investigations on the possible occurrence of an immune system messenger, interleukin-1 (IL-1), in the nervous system. This cytokine had been shown to have several effects on the nervous system, such as inducing fever (Stitt, 1981; Bligh, 1982; Dascombe, 1985) and slow wave sleep (Krueger et al., 1984; Tobler et al., 1984). Furthermore, IL-1 was chosen because it is one of the first substances to be released upon infection and inflammation (see Dinarello, 1984). There are also several studies that strongly indicate a role for IL-1 in the hormonal interactions between the hypothalamus, the pituitary and the adrenal gland. Both the glucocorticoid and gonadal hormone secretion is affected by administration of IL-1 (see Dunn, 1990). Another important activity related to IL-1 is its proliferative effects, especially in the nervous system. It has been shown to stimulate glial proliferation (cf. Nieto-Sampedro and Berman, 1987), particularly of astrocytes, and has also been demonstrated to induce translation and transcription of nerve growth factor (NGF) (Lindholm et al., 1987). Induction by IL-1 of NGF and NGF mRNA has been shown to occur both in a peripheral nerve upon sectioning, and in the central nervous sytem (Spranger et al., 1990).

In the following, a description of the morphological data on the occurrence of IL-1 in the peripheral and central nervous system is presented, with special reference to the role of IL-1 in the hypothalamo-pituitary-adrenocortical axis and as a neuronal growth factor.

1.1 IL-1 in the peripheral nervous system

Immunohistochemical studies using antisera raised against synthetic peptides (IL-1α_169-194 and IL-1α_201-215) of the murine IL-1α precursor protein (Lomedico et al., 1984) revealed the occurrence of IL-1 immunoreactive material mainly in the peripheral nervous system (Schultzberg et al., 1987). A general finding was the occurrence of varicose, IL-1 immunoreactive fibres around blood vessels, in close relation to the vascular wall (Figs. 1.1C, 1.2B). The appearance and distribution of these fibres strongly resembles the noradrenergic innervation of blood vessels. Double staining experiments indicated that the IL-1 immunoreactive material coexists with neuropeptide Y (NPY) (Schultzberg et al., in preparation), a neuropeptide which is known to occur in noradrenergic sympathetic neurons (Lundberg et al., 1982). The possibility that IL-1 released from nerve fibres innervating blood vessels has a vasoactive action has yet to be demonstrated. However, IL-1 has been shown to stimulate proliferation of vascular smooth muscle cells (Bonin et al., 1989).

Fig. 1.1A–E Immunofluorescence micrographs of sections of the rat adrenal gland (A, B), urinary bladder (C) and rat PC12 cells (D, E), after incubation with antiserum to mIL-1α_169-194 (A, C), PNMT (B) and holo mIL-1α (D). IL-1 immunoreactive cells are observed in the adrenal medulla (A), corresponding to PNMT-negative (B) and hence noradrenergic chromaffin cells (arrows in A and B). Intense immunoreaction to IL-1 is seen in the NGF-treated PC12 cells (D). Cells incubated with control serum lacked this immunoreaction (E). Numerous IL-1 immunoreactive nerve fibres can be seen in the smooth muscle layers (sm), and surrounding both an artery (a) and vein (V) in the wall of the urinary bladder (C).

Fig. 1.2 A–E Immunofluorescence micrographs of sections of the rat colon (A, D), spleen (B), hypothalamus (C) and pituitary gland (E), after incubation with antiserum to mIL-1α_169-194 (A-D) and a synthetic peptide of the IL-1 receptor (E). Abundant IL-1 immunoreactive nerve fibres can be seen in the mucosa (A), smooth muscle layers (D) and enteric plexuses (arrow in D) of the colon. Note fibres around the basis of the glands (gl) in the mucosa and in the lamina muscularis mucosa (1mm) (A). Many IL-1 positive fibres are observed around blood vessels both in the red and white pulp (arrow in B) of the spleen (b trabecular vein). A few weakly fluorescent neurons are seen in the anterior hypothalamic nucleus (arrows in C). Short, varicose fibres are emanating from the cell bodies. A dense IL-1 immunoreaction is noted in the intermediate lobe of the pituitary gland (E).

Location of IL-1 immunoreactive nerve fibres around blood vessels was also noted in the lymphatic organs (Schultzberg et al., 1987). These fibres were particularly abundant around blood vessels supplying the spleen (Fig. 1.2B), both in the red and white pulp. It is possible that some of the IL-1 positive fibres in the spleen and other lymphatic organs are connecting to immunocompetent cells, similar to the findings by Bulloch (1985) and Feiten et al. (1985) with regard to the cholinergic, noradrenergic and peptidergic innervation.

IL-1 immunoreactive nerve fibres also occur in other tissues. Many varicose fibres can be seen in the smooth muscle layers of the gastrointestinal tract and the urogenital tract (Figs 1.1C, 1.2D), and there are also fibres surrounding the nerve cell bodies in the myenteric and submucous plexus of the digestive tract (Fig. 1.2D) (Schultzberg et al., 1987). These fibres may represent postganglionic sympathetic fibres where noradrenaline and IL-1 are thus colocalized. Alternatively, they may originate in intrinsic myenteric and submucosal ganglion cells, where IL-1 would coexist with acetylcholine and a number of neuropeptides (see Furness and Costa, 1980; Schultzberg et al., 1980). In the thick muscular wall of the vas deferens, the distribution and appearance of the IL-1 positive fibres show a strong resemblance to the noradrenergic innervation of this tissue. To our knowledge there is no information on the possible action of IL-1 in these sites. It is not known whether IL-1 acts on, for example, the muscle layers in the gut by inducing contraction or relaxation, either directly on the smooth muscle or via actions on intrinsic or extrinsic enteric innervation. IL-1 released from nerves in the gut should also be considered as a possible factor in inflammatory diseases of this organ. Furthermore, IL-1 immunoreactive fibres were observed in the gastrointestinal mucosa, where some fibres surround the glands (Fig. 1.2A). It is interesting to note that IL-1 may affect mucosal secretion (Han et al., 1987).

Nerve fibres immunoreactive to IL-1 have recently been observed in rat long bones (Bjurholm et al., 1991). These fibres are located predominantly in the vicinity of, or within, blood vessel walls, both in epiphyseal and diaphyseal bone, including bone marrow, periost and adjoining connective tissue. However, IL-1 immunoreactive fibres were also frequently observed in the epiphyseal growth plate near the cartilage, both in close relation to blood vessels and without apparent vascular relationship. This distribution closely resembles the autonomic innervation described previously (Bjurholm et al., 1988). The occurrence of intraosseal nerves containing IL-1-like immunoreactivity is interesting in view of its potent effects on bone. Both inhibitory and stimulatory a...

Table of contents

• Cover image
• Title page
• Table of Contents
• Pergamon studies in neuroscience No 5
• Copyright
• FOREWORD
• Chapter 1: Location of interleukin-1 in the nervous system
• Chapter 2: Brain interleukin-1 receptors: mapping, characterization and modulation
• Chapter 3: Interleukin-1β activation of the central nervous system
• Chapter 4: Electrophysiological studies of the effects of interleukin-1 and α-interferon on the EEG and pituitary-adrenocortical activity
• Chapter 5: The immune-hypothalamo-pituitary adrenal axis: Its role in immunoregulation and tolerance to self-antigens
• Chapter 6: The pyrogenic action of cytokines
• Chapter 7: Metabolic responses to interleukin-1
• Chapter 8: Behavioural effects of cytokines
• Chapter 9: Interleukin-1 involvement in the regulation of sleep
• Chapter 10: Regulation of the synthesis of nerve growth factor (NGF) by interleukin-1 (IL-1): facts and questions
• Chapter 11: Cytokines and neuronal degeneration
• INDEX