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The expression of clock genes  ARNTL2, NPAS2  and  DEC2  are disturbed in rheumatoid arthritis, an autoimmune disease with circadian variation of symptoms. We have shown that TNF is a potent inducer of these genes. We investigated the regulation of  ARNTL2  and  NPAS2  by TNF and elucidated their effect on other clock gene expressions. Additionally, we studied the effect of  DEC1  and  DEC2  on  ARNTL, ARNTL2  and  NPAS2 . Cultured primary human fibroblasts were stimulated with TNF and the effects on ARNTL2 and NPAS2 were studied with RT-qPCR and immunofluorescence staining. The role of NF-κB was analyzed using IKK-2 inhibitor IMD-0354. TNF promoted ARNTL2 localization into the nuclei. Similar to  DEC2 , the effects of TNF on  ARNTL2  and  NPAS2  expressions were mediated via NF-κB. Cloned  ARNTL, ARNTL2, NPAS2, DEC1  and  DEC2  were transfected into HEK293. The ARNTL2/NPAS2 dimer was a weaker inducer of  PER3  and  DBP  than ARNTL/NPAS2. ARNTL2 and NPAS2 are regulated by TNF via the same mechanism as DEC2. Compared to their paralogs they have unique effects on other circadian components. Our data suggest that these genes are responsible, at least in fibroblasts, for the accurate adaptation of circadian timekeeping in individual cells during inflammation.

DEC2 Blocks the Effect of the ARNTL2/NPAS2 Dimer on the Expression of PER3 and DBP