Clock Gene Modulation by TNF-α Depends on Calcium and p38 MAP Kinase Signaling

Abstract

A 24-h treatment with the cytokine tumor necrosis factor-alpha (TNF-alpha) suppresses transcription of E-box-driven clock genes (D-site albumin promoter binding protein, Dbp; Tyrotroph embryonic factor, Tef ; Hepatic leukemia factor, Hlf; Period homolog to Drosophila 1/2/3, Per1, Per2, and Per3) by yet unknown molecular mechanisms. The attenuation of clock genes has been suggested as a putative cause for the development of sickness behavior syndrome in infectious and autoimmune diseases. Here, the authors studied the effect of TNF-alpha at early time points (<3 h) on intracellular signaling events and clock gene expression in fibroblasts. Interaction of TNF-alpha with TNFR1 (Tnfrsf1a , CD120a, p55), but not TNFR2 (Tnfrsf1b, CD120b , p75), leads to fast downregulation of gene expression of Dbp and upregulation of negative regulators of the molecular clock, Per1 and Per2, Cryptochrome-1 (Cry1), and Differentiated embryo chondrocytes-1 (Dec1). Since the decrease of Dbp is also observed in cells deficient for Per1/Per2, Cry1/Cry2 , or Dec1, these genes are unlikely to be responsible for inhibition of Dbp. The early effect of TNF-alpha on the clock gene Per1 is dependent on p38, mitogen-activated protein kinase (MAPK), and/or calcium signaling, whereas the effect on Dbp is independent of p38 MAPK, but also involves calcium signaling. Both genes remain unaffected by the NF-kappaB and AP-1 pathway. Taken collectively these data show p38 MAPK- and calcium-dependent TNFR1-mediated transient increase of the negative regulator Per1 and an independent decrease of Dbp.

Tumor Necrosis Factor and Transforming Growth Factor β Regulate Clock Genes by Controlling the Expression of the Cold Inducible RNA-binding Protein (CIRBP)

“…Moreover, TNF inhibited the expression of E-box reporter constructs of the Dbp gene that was co-transfected with plasmids expressing CLOCK and BMAL1 proteins; the expression of mutated E-box reporter constructs was not altered by TNF (17). Studies using fibroblasts with a deletion of either Per1 and Per2 or Cry1 and Cry2 ruled out the possibility that TNF activates the repressor loop mediated by PER-CRY complexes (31).…”

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).…”

The daily rhythm of mice

“…Furthermore, Bmal1 appears to regulate the development of B-cells [97] and in macrophages a circadian clock controls inflammatory immune responses [98]. Interestingly, IFN-c affects electrical activity and clock gene expression in SCN neurons [99] and tumor necrosis factor alpha (TNF-alpha) suppresses expression of clock genes by interfering with E-box mediated transcription [100] depending on calcium and p38 MAP kinase signaling [101]. These findings indicate a feedback regulation between the circadian and the immune system.…”