A. B. Cady

Interleukin-6 is pyrogenic but not somnogenic.

Interleukin-6 (IL6) induces acute phase protein production and is hypothesized to mediate systemic and central effects of IL1. To determine whether IL6 possesses somnogenic properties, rabbits were injected intracerebroventricularly with IL6; sleep-wake activity was determined and brain temperatures recorded for 6 hr. IL6 induced fever in a dose-related manner with no effect on sleep-wake activity. IL6, therefore, is the first cytokine reported to elicit fever without promoting sleep. We conclude that the somnogenic action of IL1 is not mediated through IL6.

Prolactin, vasoactive intestinal peptide, and peptide histidine methionine elicit selective increases in REM sleep in rabbits

The purpose of these experiments was to determine whether (1) vasoactive intestinal peptide (VIP) produces effects on rabbit sleep similar to those reported for rats and cats; (2) peptide histidine methionine (PHM), a peptide closely related to VIP, mimics the sleep effects of VIP; and (3) pituitary prolactin (PRL), a pituitary hormone that has a sleep-related secretory pattern and for which VIP and PHM act as releasing factors, has similar effects on sleep. VIP or PHM (0.01, 0.1 and 1.0 nmol/kg) was intracerebroventricularly (i.c.v.) injected; PRL (ovine PRL, 45 and 200 IU/kg) was subcutaneously (s.c.) administered. Sleep-wake activity and brain temperature were recorded for 6 h. For controls, rabbits received artificial cerebrospinal fluid i.c.v. or PRL-vehicle s.c. VIP and PHM promoted rapid eye movement sleep (REMS), although these effects were not dose-dependent. In addition, the high dose of VIP and PHM transiently increased wakefulness. Increases in REMS occurred only during hours 2-6 after i.c.v. injection of VIP and peptide histidine leucine (PHI). After s.c. injection of PRL, REMS started to increase in postinjection hour 3. The effect of the high dose was significantly more pronounced than that of the small dose. Each substance enhanced the frequency of REMS episodes, and the high dose of PRL also increased the duration of REMS bouts. These results are consistent with the hypothesis that VIP is involved in physiological regulation of REMS, and that the VIP- and PHM-induced increases in REMS may be mediated via release of PRL.

Interleukin-1-induced sleep and febrile responses differentially altered by a muramyl dipeptide derivative

Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine; AcMur-L-Ala-D-iGln; MDP) is a somnogenic, pyrogenic, and immunoadjuvant component of bacterial cell wall peptidoglycan. It enhances the production of the cytokine interleukin 1 (IL-1) in vivo and in vitro; IL-1 itself is somnogenic and pyrogenic. The pyrogenic effects of IL-1 may be separated from its somnogenicity by the use of antipyretics. A methyl ester derivative of MDP (murametide; AcMur-L-Ala-D-Gln-alpha-methyl ester) blocks IL-1-induced fever, but induces IL-1 production/release. Therefore, the effects of murametide on IL-1-induced sleep and fever responses were determined. Rabbits were pretreated with intravenous injections of murametide 0, 30 or 60 min before intravenous injection of a pyrogenic/somnogenic dose of recombinant IL-1 beta (rIL-1 beta). Murametide alone produced no effects on sleep or brain temperatures. Murametide given simultaneously with rIL-1 beta potentiated increases of brain temperatures, whereas when there was a 60 min delay between the injection of murametide and rIL-1 beta, responses were similar to those induced by rIL-1 beta alone. Murametide given 30 min before rIL-1 beta, blocked the expected IL-1-induced fevers but not the rIL-1 beta-mediated increases of slow-wave sleep and decreases of rapid-eye-movements sleep. These results reinforce the conclusion that, in part, independent brain mechanisms are involved in the somnogenic and pyrogenic actions of IL-1.

Enhancement of Mammalian Sleep by Immune Modulators

ABSTRACT The central nervous and immune systems are closely interwoven in host defense and share many regulatory substances. Yet, despite the common observation of sleepiness during infectious disease, it was only recently shown that sleep is altered during bacterial infection. Bacterial components that may, in part, induce this somnogenic effect include muramyl peptides (MPs) derived from cell wall peptidoglycan and endotoxin or its lipid A moiety; animals respond to certain MPs or lipid As with excess SWS. Poly I:C, a synthetic dsRNA, also enhances SWS; thus, viral products may also alter sleep-wake cycles as well. These bacterial/viral products may exert their somnogenic actions, in part, via altered cytokine production and release. Interleukin-1 β (IL1 β ), tumor necrosis factor (TNF), and interferon α 2 (INF) enhance SWS and are produced by brain cells. IL1 β -mRNA is found in normal brain. This, plus data suggesting that MPs may be constituents of normal tissue that are produced during macrophage processing of bacterial cell walls, suggests these immune response modifiers may be important in regulating normal sleep, as well as being involved in the enhanced SWS observed during infectious disease. Cytokines are linked to neuroendocrine substances that may be involved in sleep regulation. For example, IL1 β enhances growth hormone (GH) release; GH is tightly coupled to SWS in humans, and GH-releasing factor (GRF) enhances sleep. IL1 β and IL1 α cause corticotropin-releasing hormone (CRF) release; CRF induces adrenocorticotropin hormone (ACTH) release. ACTH and α-melanocyte-stimulating hormone (ACTH 1-13, α MSH), inhibit sleep, and α MSH antagonizes IL1 β -enhanced SWS. Thus, several factors may work together as a multi-level network of biochemical pathways to regulate sleep-wake cycles.