Circadian Rhythms

Sleepy Time with TNF-α

Science's STKE  07 Aug 2007:
Vol. 2007, Issue 398, pp. tw280
DOI: 10.1126/stke.3982007tw280

Why is it that soon after being exposed to an infectious agent we suffer from fatigue as well as fever? Part of the innate immune response to microbial infections is the production of proinflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). Previous studies have implicated TNF-α as a causative agent of fatigue in humans and mice; however, the mechanism is not known. Sleep is regulated by circadian mechanisms that include a negative feedback system involving the Per transcriptional repressors, the abundance of which is controlled by the transcription factors BMAL1 and CLOCK, whose expression is in turn controlled by the Per repressors. Cavadini et al. treated synchronized NIH 3T3 fibroblasts with TNF-α and observed a dose-dependent decrease in the expression of the transcriptional repressor genes Per1, Per2, and Per3 compared with untreated cells, as assessed by real-time reverse transcription polymerase chain reaction (RT-PCR) analyses. The effect of TNF-α on Per gene expression was shared by IL-1β but not by interferon-α (IFN-α) or IL-6, two other proinflammatory cytokines that are produced upon microbial infection. Clock gene expression was unaffected by TNF-α treatment. Using fibroblasts transfected with luciferase reporter genes, the authors demonstrated that TNF-α treatment inhibited expression of circadian genes under the control of promoters that contained an E-box motif--a helix-loop-helix transcription factor-binding site. Per genes, which were inhibited by TNF-α, contain E-box motifs, whereas Bmal1 and Clock genes, which were not affected by TNF-α, do not. Mice were treated with TNF-α every day for 7 days, and RT-PCR analysis of the liver showed decreased expression of Per3 and other genes regulated by circadian processes, such as Dbp, which encodes the transcription factor Dbp that contributes to circadian control of locomotor activity. TNF-α treatment of mice also decreased Dbp expression in the hypothalamus. By monitoring running-wheel activity, Cavadini et al. showed that administration of TNF-α to mice reduced their movements and increased the amount of time that the mice spent resting. Together, these data suggest that TNF-α, produced during the initial stages of microbial infections and associated with autoimmune disorders such as rheumatoid arthritis, alters circadian signaling and induces fatigue. Clinical intervention to prevent this may help patients overcome the disruptive effects of TNF-α on their sleep patterns.

G. Cavadini, S. Petrzilka, P. Kohler, C. Jud, I. Tobler, T. Birchler, A. Fontana, TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc. Natl. Acad. Sci. U.S.A. 104, 12843-12848 (2007). [Abstract] [Full Text]