TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription.
Production of TNF-alpha and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-alpha and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-alpha on the circadian timing system. TNF-alpha is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-alpha on clock genes is shared by IL-1beta, but not by IFN-alpha, and IL-6. Furthermore, TNF-alpha interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-alpha is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-alpha and IL-1beta, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.
Cavadini
Gionata
G
Division of Clinical Immunology, University Hospital Zurich, Haeldeliweg 4, CH-8044 Zurich, Switzerland.
Petrzilka
Saskia
S
Kohler
Philipp
P
Jud
Corinne
C
Tobler
Irene
I
Birchler
Thomas
T
Fontana
Adriano
A
D000818:Animals; D001522:Behavior, Animal; D056926:CLOCK Proteins; D002453:Cell Cycle; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D024721:E-Box Elements / Q000235:genetics*; D005347:Fibroblasts; D007372:Interferons / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D041681:NIH 3T3 Cells; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D053583:Interleukin-1beta; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D007372:Interferons; D056926:CLOCK Proteins; C538944:Clock protein, mouse