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

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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.

1.1 IL-1 in the peripheral nervous system

Immunohistochemical studies using antisera raised against synthetic peptides (IL-1α169-194 and IL-1α201-215) 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).

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 actions of IL-1 have been demonstrated in osteoclasts as well as osteoblasts (Gowen et al., 1983; Ikeda et al., 1988; Stashenko et al., 1987).

1.2 IL-1 and the hypothalamo-pituitary-adrenocortical axis

Administration of IL-1 stimulates an increase in plasma levels of both corticotropin releasing factor (CRF) and adrenal corticotrophic hormone (ACTH) (Berkenbosch et al., 1987;...