Department of Biophysics, Graduate School of Health Science, Kobe University, Japan.
J Immunol. 2010 Feb 1;184(3):1560-5. doi: 10.4049/jimmunol.0903284. Epub 2009 Dec 30.
The mammalian clock genes, Period and Cryptochrome (Cry), regulate circadian rhythm. We show that circadian rhythmicity and rhythmic expression of Period in the nuclei of inflammatory synovial cells and spleen cells are disturbed in mouse models of experimental arthritis. Expressions of other clock genes, Bmal1 and Dbp, are also disturbed in spleen cells by arthritis induction. Deletion of Cry1 and Cry2 results in an increase in the number of activated CD3(+) CD69(+) T cells and a higher production of TNF-alpha from spleen cells. When arthritis is induced, Cry1(-/-)Cry2(-/-) mice develop maximal exacerbation of joint swelling, and upregulation of essential mediators of arthritis, including TNF-alpha, IL-1beta and IL-6, and matrix metalloproteinase-3. Wee-1 kinase is solely upregulated in Cry1(-/-)Cry2(-/-) mice, in line with upregulation of c-Fos and Wee-1 kinase in human rheumatoid arthritis. The treatment with anti-TNF-alpha Ab significantly reduced the severity and halted the progression of the arthritis of Cry1(-/-)Cry2(-/-) mice and vice versa, ectopic expression of Cry1 in the mouse embryonic fibroblast from Cry1(-/-)Cry2(-/-) mice significantly reduced the trans activation of TNF-alpha gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease.
哺乳动物的时钟基因 Period 和 Cryptochrome（Cry）调节昼夜节律。我们发现，在实验性关节炎的小鼠模型中，炎症性滑膜细胞和脾细胞的核内昼夜节律性和 Period 的节律性表达受到干扰。关节炎诱导也会干扰脾细胞中其他时钟基因 Bmal1 和 Dbp 的表达。Cry1 和 Cry2 的缺失导致 CD3(+)CD69(+)T 细胞的激活数量增加，并且 TNF-α的产生增加从脾细胞。当关节炎被诱导时，Cry1(-/-)Cry2(-/-)小鼠出现关节肿胀的最大恶化，以及关节炎的必需介质的上调，包括 TNF-α、IL-1β 和 IL-6 以及基质金属蛋白酶-3。Wee-1 激酶仅在 Cry1(-/-)Cry2(-/-)小鼠中上调，与人类类风湿关节炎中 c-Fos 和 Wee-1 激酶的上调一致。抗 TNF-α Ab 的治疗显著降低了 Cry1(-/-)Cry2(-/-)小鼠关节炎的严重程度并阻止了其进展，反之亦然，从 Cry1(-/-)Cry2(-/-)小鼠的小鼠胚胎成纤维细胞中外源表达 Cry1 显著降低了 TNF-α基因的反式激活。因此，生物钟和关节炎相互影响，这种相互作用会影响人类的健康和疾病。
