Mammalian clock gene Cryptochrome regulates arthritis via proinflammatory cytokine TNF-α

Akira Hashiramoto, Takashi Yamane, Ken Tsumiyama, Kohsuke Yoshida, Koichiro Komai, Hiroyuki Yamada, Fumiyoshi Yamazaki, Masao Doi, Hitoshi Okamura, Shunichi Shiozawa

Research output: Contribution to journalArticlepeer-review

155 Citations (Scopus)


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-α 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-α, IL-1β 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-α 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-α gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease.

Original languageEnglish
Pages (from-to)1560-1565
Number of pages6
JournalJournal of Immunology
Issue number3
Publication statusPublished - Feb 1 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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