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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Blaikley, John Gibbs, Julie E. Matthews, Laura Ray, David W. Boyce, Susan H. Beesley, Stephen Simpson, Karen D. Loudon, Andrew S. I. Farrow, Stuart N. Else, Kathryn J. Singh, Dave |
| Description | Author Affiliation: Gibbs JE ( Faculty of Life Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PT, United Kingdom.); |
| Abstract | Diurnal variation in inflammatory and immune function is evident in the physiology and pathology of humans and animals, but molecular mechanisms and mediating cell types that provide this gating remain unknown. By screening cytokine responses in mice to endotoxin challenge at different times of day, we reveal that the magnitude of response exhibited pronounced temporal dependence, yet only within a subset of proinflammatory cytokines. Disruption of the circadian clockwork in macrophages (primary effector cells of the innate immune system) by conditional targeting of a key clock gene (bmal1) removed all temporal gating of endotoxin-induced cytokine response in cultured cells and in vivo. Loss of circadian gating was coincident with suppressed rev-erb expression, implicating this nuclear receptor as a potential link between the clock and inflammatory pathways. This finding was confirmed in vivo and in vitro through genetic and pharmacological modulation of REV-ERB activity. Circadian gating of endotoxin response was lost in rev-erb (-/-) mice and in cultured macrophages from these animals, despite maintenance of circadian rhythmicity within these cells. Using human macrophages, which show circadian clock gene oscillations and rhythmic endotoxin responses, we demonstrate that administration of a synthetic REV-ERB ligand, or genetic knockdown of rev-erb expression, is effective at modulating the production and release of the proinflammatory cytokine IL-6. This work demonstrates that the macrophage clockwork provides temporal gating of systemic responses to endotoxin, and identifies REV-ERB as the key link between the clock and immune function. REV-ERB may therefore represent a unique therapeutic target in human inflammatory disease. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Circadian Rhythm Immunology Gene Expression Regulation Immunity, Innate Interleukin-6 Nuclear Receptor Subfamily 1, Group D, Member 1 ARNTL Transcription Factors Genetics Analysis Of Variance Animals Endotoxins Toxicity Macrophages Mice Mice, Knockout Time Factors Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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