Clock gene modulation by TNF-alpha depends on calcium and p38 MAP kinase signaling.
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.
Petrzilka
Saskia
S
Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland.
Taraborrelli
Cornelia
C
Cavadini
Gionata
G
Fontana
Adriano
A
Birchler
Thomas
T
D000818:Animals; D001683:Biological Clocks / Q000235:genetics*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D056931:Cryptochromes; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C538963:CRY1 protein, human; C538966:CRY2 protein, human; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; D056931:Cryptochromes; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C539022:PER1 protein, human; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; D002118:Calcium