title: Mechanism of the 24-hour rhythm of tumor necrosis factor-alpha formed by onset of rheumatoid arthritis.
abstract: OBJECTIVE
  Morning stiffness and plasma cytokine levels in rheumatoid arthritis (RA) patients exhibit 24-hour variations. Tumor necrosis factor-α (TNF-α) plays a central role in RA clinical conditions, including the invasion of inflammatory cells, destruction of cartilage, systemic inflammatory response and its levels show a 24-hour rhythm after the onset of RA. In this study, we investigated what cytokines and/or transcriptional factors are involved in the formation of 24-hour variations in TNF-α levels after the onset of RA using MRL/Mpj-Tnfrsf6(lpr) (MRL/lpr) mice.
  
  
  METHODS
  Blood was drawn at six different times from MRL/lpr mice to measure cytokines, serum amyloid A (SAA), IgG rheumatoid factor (IgG-RF) and corticosterone levels. Cytokine and transcriptional factor levels at the different times were measured in 10- and/or 15-week-old MRL/lpr mice. The promoter activity of TNF-α by lymphotoxins (LTs) was investigated using a dual-luciferase assay.
  
  
  RESULTS
  SAA and TNF-α concentrations clearly exhibited 24-hour rhythms with higher levels at the light phase and lower levels at the dark phase after RA crisis. The expression of LT-α and LT-β showed significant 24-hour rhythms in 15-week-old MRL/lpr mice and the phases of LT-α and LT-β levels were antiphase compared with that of TNF-α. AP-1 binding sites were found in LT-α and LT-β promoter regions, and jun mRNA expression corresponded to LT-α and LT-β levels. TNF-α promoter activity was decreased due to the co-transfection of LT-α and LT-β.
  
  
  CONCLUSIONS
  LT-α and LT-β controls the 24-hour rhythm in TNF-α levels after the onset of RA in order to suppress TNF-α promoter activity.
authors: Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University , Fukuoka , Japan and.
authors: Hiromichi
authors: H
authors: Yoshimatsu
authors: Fumiyasu
authors: F
authors: Okazaki
authors: Ichiro
authors: I
authors: Ieiri
authors: Hideto
authors: H
authors: To
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D015536:Down-Regulation; D018836:Inflammation Mediators / Q000097:blood*; D008233:Lymphotoxin-alpha / Q000097:blood; D053308:Lymphotoxin-beta / Q000097:blood; D008297:Male; D019463:Mice, Inbred MRL lpr; D011401:Promoter Regions, Genetic; D000685:Serum Amyloid A Protein / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha