TNF-α suppresses the expression of clock genes by interfering with E-box-mediated transcription

Abstract

Production of TNF-␣ 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-␣ 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-␣ on the circadian timing system. TNF-␣ is shown here to suppress the expression of the PAR bZip clockcontrolled 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-␣ on clock genes is shared by IL-1␤, but not by IFN-␣, and IL-6. Furthermore, TNF-␣ 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-␣ 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-␣ and IL-1␤, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.behavior ͉ circadian rhythms ͉ cytokines ͉ innate immunity

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

“…These data also suggest that anticytokine therapy targeting TNF-α may achieve its (fast or rapid) clinical benefit remote from the inflamed joint through influencing CNS processes. Our findings also extend previous observations on the effects of TNF-α in the CNS (i.e., the regulation of expression of clock genes), which may explain the high prevalence of fatigue in inflammatory diseases (22). Finally, our findings also raise the possibility that the assessment of responsiveness of BOLD activity in the CNS of RA patients and patients with other forms of inflammatory arthritis may be used as a surrogate marker for predicting clinical responses to therapeutic intervention in a much faster way than it is currently realized.…”

Depression in Autoimmune Diseases

“…Besides effects of the circadian system on the immune response, the immune system also influences the circadian clock. TNF inhibits the expression of all three Period genes, of Cry-1 and -2 and of the PAR-bZip transcription factors Dbp, Tef and Hlf (Cavadini et al, 2007;Petrzilka et al, 2009). At least some of these effects are due to an interference with E-box-dependent transcription (Cavadini et al, 2007).…”

“…TNF inhibits the expression of all three Period genes, of Cry-1 and -2 and of the PAR-bZip transcription factors Dbp, Tef and Hlf (Cavadini et al, 2007;Petrzilka et al, 2009). At least some of these effects are due to an interference with E-box-dependent transcription (Cavadini et al, 2007). Both TNF induced Twist1 expression and TNF-mediated inhibition of the cold-inducible RNA binding protein (CIRBP) are involved in immune mediated dysregulation of clock genes (Lopez et al, 2014;Meier et al, 2015).…”

Immunometabolism: Is it under the eye of the clock?

“…Bmal1 itself is regulated by the innate immune response, as activation of macrophages induces the expression of the microRNA miR-155 that targets Bmal1 mRNA for degradation [14]. Similarly, TNF␣ suppresses clock gene expression by interfering with E-box mediated transcription [81]. The inflammatory response may in fact slow down or stop the clock.…”