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

Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland

Cornelia Taraborrelli

Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland

Gionata Cavadini

Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland

Adriano Fontana

Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland

Thomas Birchler

Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland, thomas.birchler{at}usz.ch

A 24-h treatment with the cytokine tumor necrosis factor- (TNF-) 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- at early time points (<3 h) on intracellular signaling events and clock gene expression in fibroblasts. Interaction of TNF- 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- 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-B 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.

Key Words: tumor necrosis factor- • cytokines • clock gene regulation • inflammation • D-site albumin promotor binding protein • calcium • p38 map kinase

Journal of Biological Rhythms, Vol. 24, No. 4, 283-294 (2009)
DOI: 10.1177/0748730409336579


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