Erschienen:
Proceedings of the National Academy of Sciences, 2007
Erschienen in:Proceedings of the National Academy of Sciences
Sprache:
Englisch
DOI:
10.1073/pnas.0701466104
ISSN:
0027-8424;
1091-6490
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>
Production of TNF-α 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-α 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-α on the circadian timing system. TNF-α is shown here to suppress the expression of the PAR bZip clock-controlled genes
<jats:italic>Dbp</jats:italic>
,
<jats:italic>Tef</jats:italic>
, and
<jats:italic>Hlf</jats:italic>
and of the period genes
<jats:italic>Per1</jats:italic>
,
<jats:italic>Per2</jats:italic>
, and
<jats:italic>Per3</jats:italic>
in fibroblasts
<jats:italic>in vitro</jats:italic>
and
<jats:italic>in vivo</jats:italic>
in the liver of mice infused with the cytokine. The effect of TNF-α on clock genes is shared by IL-1β, but not by IFN-α, and IL-6. Furthermore, TNF-α interferes with the expression of
<jats:italic>Dbp</jats:italic>
in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-α 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-α and IL-1β, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.
</jats:p>