title: Adenosine A2A receptor and TNF-α regulate the circadian machinery of the human monocytic THP-1 cells.
abstract: Morning stiffness and increased symptoms of inflammatory arthritis are among the most common manifestations of rheumatoid arthritis (RA). Tumor necrosis alpha (TNF-α), an important mediator of inflammation in RA, regulates the circadian expression of clock proteins, and adenosine A(2A) receptors (A(2A)R) mediate many of the anti-inflammatory and antirheumatic actions of methotrexate, the cornerstone drug in the treatment of RA. We found that A(2A)R activation and TNF-α activated the clock core loop of the human monocytic THP-1 cell line. We further observed that interleukin (IL)-10, but not IL-12, mRNA expression fluctuates in a circadian fashion and that TNF-α and A(2A)R stimulation combined increased IL-10 expression. Interestingly, TNF-α, but not CGS21680, dramatically inhibited IL-12 mRNA expression. The demonstration that A(2A)R and TNF-α regulate the intrinsic circadian clock in immune cells provides an explanation for both the pathologic changes in circadian rhythms in RA and for the adverse circadian effects of methotrexate, such as fatigue.
authors.affiliation: Division of Translational Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. Miguel.PerezAso@nyumc.org
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez-Aso
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Feig
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Mediero
authors.forename: Mediero
authors.initials: M
authors.lastname: Aránzazu
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D056926:CLOCK Proteins / Q000378:metabolism*; D002460:Cell Line; D057906:Circadian Clocks; D002940:Circadian Rhythm; D056931:Cryptochromes / Q000096:biosynthesis; D005221:Fatigue; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008727:Methotrexate / Q000494:pharmacology* / Q000627:therapeutic use; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D056950:Period Circadian Proteins / Q000096:biosynthesis; D010627:Phenethylamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538963:CRY1 protein, human; D056931:Cryptochromes; D007375:Interleukin-1; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D010627:Phenethylamines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D016753:Interleukin-10; D056926:CLOCK Proteins; D000241:Adenosine; D008727:Methotrexate