The circadian clock Period 2 gene regulates gamma interferon production of NK cells in host response to lipopolysaccharide-induced endotoxic shock.
The Period 2 (Per2) gene is a key molecular component in controlling mammalian circadian rhythms at the levels of gene expression, physiology, and pathogenesis. Although many immune parameters, such as the number of different subtypes of circulating immune cells and the level of cytokine production in response to infection with bacteria and viruses, have been well documented to display a circadian pattern in mammals, the basic features of molecular clock components in the immune system and the role of clock genes in regulating host immune defenses remain uncharacterized. Previously, we have reported that circadian clock genes oscillate in human mononuclear cells. Here we report that Per2-deficient mice were more resistant to lipopolysaccharide (LPS)-induced endotoxic shock than control wild-type mice. We further demonstrate that the levels of the proinflammatory cytokines gamma interferon (IFN-gamma) and interleukin-1beta (IL-1beta) in the serum were dramatically decreased in Per2-/- mice following LPS challenge, while production of tumor necrosis factor alpha, IL-6, and IL-10 was approximately normal, compared to that in control wild-type mice. Flow cytometric analyses confirmed that the cellularity of most of the immune cell subsets in the spleens of LPS-challenged mice was normal and that the impaired IFN-gamma production in Per2-/- mice was attributable to defective NK and NKT cell function. Our data suggest that Per2 is an important regulator of NK cell function, therefore providing the first direct link between the circadian clock system and innate immune responses.
Liu
Jianguo
J
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
Malkani
Gautam
G
Mankani
Guantham
G
Shi
Xiaoyan
X
Meyer
Mark
M
Cunningham-Runddles
Susana
S
Ma
Xiaojing
X
Sun
Zhong Sheng
ZS
D000818:Animals; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D056950:Period Circadian Proteins; D012772:Shock, Septic / Q000209:etiology / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics
D018797:Cell Cycle Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D007371:Interferon-gamma