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Interleukin-1-induced sleep and febrile responses differentially altered by a muramyl dipeptide derivative
1Department of Physiology and Biophysics, University of Tennessee, Memphis 38163.
Abstract:
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.
Insights
Muramyl dipeptide (MDP) derivative, murametide, separates interleukin-1 (IL-1)-induced fever from sleep responses. This suggests distinct brain mechanisms control IL-1
Area of Science:
- Neuroscience
- Immunology
- Sleep Science
Background:
- Muramyl dipeptide (MDP) is a bacterial cell wall component known for somnogenic, pyrogenic, and immunoadjuvant properties.
- Interleukin-1 (IL-1) is a cytokine that mediates somnogenic and pyrogenic effects, with its fever-inducing actions potentially separable from sleep-inducing effects.
- A methyl ester derivative of MDP, murametide, inhibits IL-1-induced fever while still inducing IL-1 production.
Purpose of the Study:
- To investigate the effects of murametide on IL-1-induced sleep and fever responses in rabbits.
- To determine if murametide can dissociate the somnogenic and pyrogenic actions of IL-1.
Main Methods:
- Rabbits received intravenous injections of murametide at varying times (0, 30, or 60 minutes) prior to recombinant IL-1 beta (rIL-1 beta).
- Sleep patterns (slow-wave sleep, rapid-eye-movement sleep) and brain temperatures were monitored.
- Control groups received murametide or rIL-1 beta alone.
Main Results:
- Murametide alone did not affect sleep or brain temperature.
- Co-administration of murametide with rIL-1 beta potentiated fever, while a 60-minute delay resulted in responses similar to rIL-1 beta alone.
- Murametide administered 30 minutes before rIL-1 beta blocked fever but not the alterations in sleep patterns induced by rIL-1 beta.
Conclusions:
- Murametide effectively separates the fever and sleep effects of IL-1.
- These findings support the hypothesis that distinct neural mechanisms underlie the somnogenic and pyrogenic actions of IL-1.
- The timing of murametide administration is critical in modulating the differential effects of IL-1.