PMID- 24517140 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20151119 IS - 1525-6073 (Electronic) IS - 0742-0528 (Linking) VI - 31 IP - 4 DP - 2014 May TI - Mechanism of the 24-hour rhythm of tumor necrosis factor-alpha formed by onset of rheumatoid arthritis. PG - 564-71 LID - 10.3109/07420528.2013.878350 [doi] AB - OBJECTIVE: Morning stiffness and plasma cytokine levels in rheumatoid arthritis (RA) patients exhibit 24-hour variations. Tumor necrosis factor-alpha (TNF-alpha) 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-alpha levels after the onset of RA using MRL/Mpj-Tnfrsf6(lpr) (MRL/lpr) mice. METHOD: 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-alpha by lymphotoxins (LTs) was investigated using a dual-luciferase assay. RESULTS: SAA and TNF-alpha 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-alpha and LT-beta showed significant 24-hour rhythms in 15-week-old MRL/lpr mice and the phases of LT-alpha and LT-beta levels were antiphase compared with that of TNF-alpha. AP-1 binding sites were found in LT-alpha and LT-beta promoter regions, and jun mRNA expression corresponded to LT-alpha and LT-beta levels. TNF-alpha promoter activity was decreased due to the co-transfection of LT-alpha and LT-beta. CONCLUSION: LT-alpha and LT-beta controls the 24-hour rhythm in TNF-alpha levels after the onset of RA in order to suppress TNF-alpha promoter activity. FAU - Yoshimatsu, Hiromichi AU - Yoshimatsu H AD - Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University , Fukuoka , Japan and. FAU - Okazaki, Fumiyasu AU - Okazaki F FAU - Ieiri, Ichiro AU - Ieiri I FAU - To, Hideto AU - To H LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140211 PL - England TA - Chronobiol Int JT - Chronobiology international JID - 8501362 RN - 0 (Biomarkers) RN - 0 (Inflammation Mediators) RN - 0 (Ltb protein, mouse) RN - 0 (Lymphotoxin-alpha) RN - 0 (Lymphotoxin-beta) RN - 0 (Serum Amyloid A Protein) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Animals MH - Arthritis, Rheumatoid/*blood/genetics/immunology MH - Biomarkers/blood MH - Cells, Cultured MH - *Circadian Rhythm MH - Disease Models, Animal MH - Down-Regulation MH - Inflammation Mediators/*blood MH - Lymphotoxin-alpha/blood MH - Lymphotoxin-beta/blood MH - Male MH - Mice, Inbred MRL lpr MH - Promoter Regions, Genetic MH - Serum Amyloid A Protein/metabolism MH - Time Factors MH - Transcription, Genetic MH - Transfection MH - Tumor Necrosis Factor-alpha/*blood/genetics EDAT- 2014/02/13 06:00 MHDA- 2015/02/13 06:00 CRDT- 2014/02/13 06:00 PHST- 2014/02/13 06:00 [entrez] PHST- 2014/02/13 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] AID - 10.3109/07420528.2013.878350 [doi] PST - ppublish SO - Chronobiol Int. 2014 May;31(4):564-71. doi: 10.3109/07420528.2013.878350. Epub 2014 Feb 11.