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

Martin Lopez; Daniel Meier; Andreas Müller; Paul Franken; Jun Fujita; Adriano Fontana

doi:10.1074/jbc.M113.508200

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

From the ^‡Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland,
the ^§Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland, and
the ^¶Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

↵2 Hertie Senior Research Professor for Neuroscience of the Gemeinnützige Hertie-Stiftung. To whom correspondence should be addressed: Institute of Experimental Immunology, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail: adriano.fontana{at}usz.ch.

↵1 Both authors contributed equally to this work.

Background: CIRBP facilitates expression of clock genes by stabilizing their transcripts.

Results: Down-regulation of expression of clock genes by TNF and TGFβ is mediated by inhibition of CIRBP production.

Conclusion: TNF and TGFβ impair the expression of Cirbp and thereby influence circadian gene expression.

Significance: A novel regulatory pathway that links immune activation with circadian gene expression is identified.

Abstract

The circadian clock drives the rhythmic expression of a broad array of genes that orchestrate metabolism, sleep wake behavior, and the immune response. Clock genes are transcriptional regulators engaged in the generation of circadian rhythms. The cold inducible RNA-binding protein (CIRBP) guarantees high amplitude expression of clock. The cytokines TNF and TGFβ impair the expression of clock genes, namely the period genes and the proline- and acidic amino acid-rich basic leucine zipper (PAR-bZip) clock-controlled genes. Here, we show that TNF and TGFβ impair the expression of Cirbp in fibroblasts and neuronal cells. IL-1β, IL-6, IFNα, and IFNγ do not exert such effects. Depletion of Cirbp is found to increase the susceptibility of cells to the TNF-mediated inhibition of high amplitude expression of clock genes and modulates the TNF-induced cytokine response. Our findings reveal a new mechanism of cytokine-regulated expression of clock genes.

Footnotes

↵* This work was supported by the Swiss National Science Foundation Project 310030_141055/1 (to A. F.), the Velux Stiftung (to A. F.), the Novartis Foundation (to A. F.), the Cancer Foundation Zurich (to A. F.), and the Smoking Research Foundation Japan (to J. F.).
↵ This article contains supplemental Tables 1 and 2.