Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 300

A stimulation of peripheral blood and subcutaneous injection in a Popliteal
Lymph Node Assay. 401 In contrast, chronic reversals of the LD cycle in mice
were found to sensitize the inflammatory response to dextran sodium sulfate,
a model of colitis. 402 Similarly, weekly 6 h shifts of the LD cycle in mice
exacerbated the immune response to lipopolysaccharide, a model for sep-
sis. 353 Repeated LD shifts also suppressed the cytotoxic activity of Natural
Killer cells and promoted the development of lung tumors. 111 Exposure
to constant light, likewise, affects immune function in rodent and avian spe-
cies. 403-405 Additionally, exposure to light at night suppresses immune func-
tion in Siberian hamsters, with chronic exposure producing reduced
delayed-type hypersensitivity and suppressed blood plasma bactericidal
activity following lipopolysaccharide challenge. 55 Seasonal changes in
immune function and responses have been documented in the Siberian
hamster. 406-409 Additionally, rapid and repeated changes in day length
results in immune dysfunction in rats, mice, and flies. 79

4.8.2 Genetic models
Clock gene expression rhythms are evident in various types of immune cells,
with local clock function important for the temporal regulation of inflam-
matory responses (reviewed in Ref. 394 ). Rev - erb a has been identified as an
important part of the mechanism by which the circadian clock regulates the
temporal gating of immune function, with rev-erb a mice displaying a

hypersensitive response to the lipopolysaccharide challenge. 410 It has also
been found that the clock gene cry negatively regulates cytokine produc-
tion 411 and mice with deletions of both cry paralogs display an immune phe-
notype, with exacerbated cytokine production and joint swelling after
arthritic induction. 412 In addition, per2 mutant mice and per1

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mice dis-
play altered cytokine and cytolytic expression rhythms in Natural Killer
cells, 413-415 with reduced responses to the lipopolysaccharide challenge in
per2 mutant mice. 416 Deletion of bmal1 in mice is associated with progressive
corneal inflammation and decreased immune cell expression. 83,417,418 Lastly,
mice with a clock null mutation display altered transcription of immune
genes 419 and reduced activation of NF- k B activation in cultured fibroblasts
and hepatocytes. 420 In genetic association studies examining the relationship
between clock gene polymorphisms and immune disorders, a link has been
identified between a specific per3 polymorphism and the incidence or sever-
ity of inflammatory bowel disease. 421

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