Mammalian Clock Gene Cryptochrome Regulates Arthritis via Proinflammatory Cytokine TNF-α
Mammalian Clock Gene Cryptochrome Regulates Arthritis via Proinflammatory Cytokine TNF-α
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DOI：
10.4049/jimmunol.0903284
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发表时间：
2010-02-01
影响因子：
4.4
通讯作者：
Shiozawa, Shunichi
中科院分区：
文献类型：
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作者：
Hashiramoto, Akira;Yamane, Takashi;Shiozawa, Shunichi
哺乳动物的生物钟基因Period和Cryptochrome（Cry）调节昼夜节律。我们发现，在实验性关节炎小鼠模型中，炎症滑膜细胞和脾细胞核中周期的昼夜节律性和节律性表达受到干扰。其他时钟基因Bmall和Dbp的表达也在脾细胞中受到关节炎诱导的干扰。Cry 1和Cry 2的缺失导致活化的CD 3（+）CD 69（+）T细胞的数量增加和脾细胞产生更高的TNF-α。当诱导关节炎时，Cry 1（-/-）Cry 2（-/-）小鼠出现关节肿胀的最大恶化，以及关节炎的基本介质（包括TNF-α、IL-1 β和IL-6以及基质金属蛋白酶-3）的上调。Wee-1激酶仅在Cry 1（-/-）Cry 2（-/-）小鼠中上调，与人类风湿性关节炎中c-Fos和Wee-1激酶的上调一致。用抗TNF-α Ab治疗显著降低了Cry 1（-/-）Cry 2（-/-）小鼠关节炎的严重程度并阻止了其进展，反之亦然，Cry 1在来自Cry 1（-/-）Cry 2（-/-）小鼠的小鼠胚胎成纤维细胞中的异位表达显著降低了TNF-α基因的反式激活。因此，生物钟和关节炎相互影响，这种相互作用可以影响人类的健康和疾病。免疫学杂志，2010，184：1560-1565。
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, Bmall 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-1 beta 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-a gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease. The Journal of Immunology, 2010, 184: 1560-1565.