title: Acute systemic inflammation transiently synchronizes clock gene expression in equine peripheral blood.
abstract: Peripheral clocks receive timing signals from the master mammalian pacemaker in the suprachiasmatic nucleus (SCN) and function to adaptively anticipate daily changes that influence local physiology. Evidence suggests that peripheral immune activation may act as a resetting signal for circadian clocks in peripheral tissues. We wished to investigate whether acute systemic inflammation could synchronize clock gene expression in equine peripheral blood, a tissue that does not normally oscillate in this species. We report that in vivo administration of lipopolysaccharide (LPS) results in significant upregulation of the core clock genes Per2 and Bmal1 in equine blood, in association with an acute rise in tumor necrosis factor (TNF) alpha and core body temperature compared to vehicle-treated control animals. Furthermore, co-administration of LPS and phenylbutazone, a non-steroidal anti-inflammatory drug (NSAID) known to inhibit prostaglandin (PG) E(2) synthesis in the horse, prevents both the febrile response and the synchronized increase in clock gene expression. However, the rise in Per2 and Bmal1 expression cannot be replicated in equine peripheral blood mononuclear cells (PBMCs) ex vivo by treatment with PGE(2), LPS or a heat shock mimicking the in vivo febrile response. These results may suggest an indirect communication pathway between immune modulators and the molecular machinery of cell clocks in peripheral blood. This potential immune feedback regulation of an equine peripheral clock implies a role for the circadian system in contributing to innate immune reactions and maintaining homeostasis in a tissue that acts as the first line of defense during an infectious challenge.
authors.affiliation: Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Lexington, KY 40546-0099, USA. babsmurphy@gmail.com
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Murphy
authors.forename: Mandi M
authors.initials: MM
authors.lastname: Vick
authors.forename: Dawn R
authors.initials: DR
authors.lastname: Sessions
authors.forename: R Frank
authors.initials: RF
authors.lastname: Cook
authors.forename: Barry P
authors.initials: BP
authors.lastname: Fitzgerald
mesh_terms: D056930:ARNTL Transcription Factors; D000222:Adaptation, Physiological; D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000097:blood; D001683:Biological Clocks / Q000235:genetics*; D001831:Body Temperature / Q000276:immunology; D002940:Circadian Rhythm / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006736:Horses; D007249:Inflammation / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D009687:Nuclear Proteins / Q000097:blood; D009991:Oscillometry; D014157:Transcription Factors / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha