Recombinant tumor necrosis factor and interleukin 1 enhance slow-wave sleep

The cytokines interleukin 1 (IL 1) and interferon (IFN) are immune response modifiers that are also pyrogenic and somnogenic. Tumor necrosis factor (TNF) (cachectin) is another pyrogenic monocyte product whose production can be elicited by somnogenic agents such as endotoxin. Human recombinant TNF (rTNF), therefore, was assayed for somnogenic activity. Intravenous (iv) or intracerebroventricular (ICV) injections of rTNF enhanced slow-wave sleep (SWS) and electroencephalographic slow-wave (0.5-4.0 Hz) activity. Recombinant TNF also suppressed rapid-eye-movement sleep (REM) and induced biphasic fevers whether given by intravenous or ICV injection. Responses to rTNF were compared with those elicited by human recombinant beta-IL 1 (rIL 1). Sleep responses elicited by rIL 1 were similar to those previously reported for native IL 1 and to those elicited by rTNF. However, unlike rTNF, rIL 1 induced monophasic fevers. Animal behavior and brain temperature changes that occur during the transition from one arousal state to another remained undisturbed after either rTNF or rIL 1 treatment. The fact that TNF and IL 1 as well as other immunoactive substances, e.g., IFN, muramyl peptides, and endotoxin, enhance SWS suggests that SWS is linked to the immune response. We conclude that TNF, in addition to IL 1 and IFN, is an endogenous somnogen.