Adenosine A(2A) Receptor and TNF-alpha Regulate the Circadian Machinery of the Human Monocytic THP-1 Cells

作者：Perez Aso Miguel^*; Feig Jessica L; Aranzazu Mediero; Cronstein Bruce N

来源：Inflammation, 2013, 36(1): 152-162.

DOI：10.1007/s10753-012-9530-x

• adenosine A2 receptor
• TNF-alpha
• IL10
• IL-12
• clock genes
• methotrexate

Morning stiffness and increased symptoms of inflammatory arthritis are among the most common manifestations of rheumatoid arthritis (RA). Tumor necrosis alpha (TNF-alpha), 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-alpha 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-alpha and A(2A)R stimulation combined increased IL-10 expression. Interestingly, TNF-alpha, but not CGS21680, dramatically inhibited IL-12 mRNA expression. The demonstration that A(2A)R and TNF-alpha 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.

• 出版日期2013-2