Biological clock dysfunction exacerbates contact hypersensitivity in mice

Br J Dermatol. 2013 Jan;168(1):39-46. doi: 10.1111/j.1365-2133.2012.11176.x. Epub 2012 Nov 2.


Background: Immediate-type skin allergic reactions, such as passive cutaneous anaphylactic reaction, are associated with circadian rhythm, but the role of circadian mechanisms on delayed-type skin allergic reactions, such as contact hypersensitivity (CHS), remains uncertain. In mice, CHS, a T-cell-mediated immune response, is a classic model of human allergic contact dermatitis.

Objectives: We investigated whether biological clock dysfunction affects CHS pathogenesis in CLOCK mutant mice compared with wild-type (WT) mice.

Methods: Mice were treated with 2,4,6-trinitro-1-chlorobenzene (TNCB) on the abdominal skin on day 0 (sensitization) and then treated with TNCB on the ears on day 5 (challenge).

Results: We found that biological clock dysfunction resulted in severe inflammation. Ear swelling, serum immunoglobulin E level and mast cell number were significantly increased in CLOCK mutant mice compared with WT mice. These results provide evidence that CLOCK mutation promotes the T-helper type 2 immune response and exacerbates CHS. Corticosterone has a protective effect on CHS. The serum corticosterone level lost rhythmicity and showed a decreased daily level in CLOCK mutant mice compared with WT mice, supporting the exacerbating effect of CLOCK mutation on CHS. Adrenalectomy markedly worsened TNCB-induced CHS in WT mice but not in CLOCK mutant mice. In addition, dramatic dexamethasone-induced protection of CHS was observed in CLOCK mutant mice compared with WT mice.

Conclusions: The present results suggest that circadian rhythm might be an important factor in the regulation of CHS via corticosterone rhythmicity and/or level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex / physiology
  • Adrenalectomy
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Biological Clocks* / genetics
  • Chronobiology Disorders / complications*
  • Corticosterone / metabolism
  • Dermatitis, Contact / etiology*
  • Dermatitis, Contact / immunology
  • Dexamethasone / pharmacology
  • Hypersensitivity, Delayed / etiology*
  • Hypersensitivity, Delayed / immunology
  • Immunity, Cellular / physiology
  • Irritants
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Mutation
  • Picryl Chloride


  • Anti-Inflammatory Agents
  • Irritants
  • Dexamethasone
  • Corticosterone
  • Picryl Chloride