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

Background: CIRBP facilitates expression of clock genes by stabilizing their transcripts. Results: Down-regulation of expression of clock genes by TNF and TGF is mediated by inhibition of CIRBP production. Conclusion: TNF and TGF 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.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 TGF 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 TGF impair the expression of Cirbp in fibroblasts and neuronal cells. IL-1, IL-6, IFN, and IFN 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.