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Timing the Immune Response

The circadian regulator CLOCK enhances the transcriptional activity of the immune regulator NF-κB. The immune response, like many physiological processes, varies with the day-night cycle. The circadian cycle is controlled by a transcriptional regulatory complex of CLOCK and BMAL1. Spengler et al. identified a connection between the immune transcriptional regulator NF-κB (nuclear factor κB) and the circadian regulatory protein CLOCK. The ability to enhance NF-κB transcriptional activity was independent from BMAL1, thus defining another partner for CLOCK. Using mice expressing an NF-κB–responsive reporter gene in the liver, the authors showed that the NF-κB response to a nontoxic agonist, CBLB502, of Toll-like receptor 5 (TLR5) was greatest when the animals were exposed during the middle of the rest period. When wild-type, Clock+/– heterozygous, or Clock–/– mice were exposed to the TLR5 ligand at the same time in the circadian cycle, Clock+/– heterozygous animals showed reduced activation of the reporter gene and Clock–/– mice showed reduced production of interleukin-6, a cytokine that is encoded by an NF-κB target gene. Analysis of NF-κB activity in transfected mammalian cell lines or in mouse embryonic fibroblasts deficient in either CLOCK or BMAL1 and transfected with various mutant proteins showed that the ability of CLOCK to enhance NF-κB–mediated transcription did not require the transactivation domain of CLOCK or BMAL1. Indeed, overexpression of BMAL1 reduced CLOCK-mediated enhancement of NF-κB activity, whereas cells deficient in BMAL1 exhibited the opposite effect. Although acetylation of the p65 subunit of NF-κB, which is associated with increased activity, was increased in cells overexpressing CLOCK, the histone acetyltransferase activity of CLOCK was not required for this effect. CLOCK and the p65 subunit of NF-κB coimmunoprecipitated in experiments performed with overexpressed proteins or with endogenous proteins. Thus, in addition to functioning as a transcriptional regulator when complexed with BMAL1, CLOCK also appears to function with NF-κB to promote circadian changes in the immune response. M. L. Spengler, K. K. Kuropatwinski, M. Comas, A. V. Gasparian, N. Fedtsova, A. S. Gleiberman, I. I. Gitlin, N. M. Artemicheva, K. A. Deluca, A. V. Gudkov, M. P. Antoch, Core circadian protein CLOCK is a positive regulator of NF-κB–mediated transcription. Proc. Natl. Acad. Sci. U.S.A. 109, E2457–E2465 (2012). [Abstract] [Full Text]