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Infection and Immunity, August 2006, p. 4750-4756, Vol. 74, No. 8
0019-9567/06/$08.00+0     doi:10.1128/IAI.00287-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Circadian Clock Period 2 Gene Regulates Gamma Interferon Production of NK Cells in Host Response to Lipopolysaccharide-Induced Endotoxic Shock

Jianguo Liu,1,{dagger} Guantham Mankani,2,{dagger} Xiaoyan Shi,1 Mark Meyer,2 Susana Cunningham-Runddles,2 Xiaojing Ma,1* and Zhong Sheng Sun2,3*

Department of Microbiology and Immunology,1 Department of Pediatrics, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021,2 Behavioral Genetics Center, The Institute of Psychology, Chinese Academy of Sciences, Datong Road 10A, Beijing, China 1001013

Received 21 February 2006/ Returned for modification 24 April 2006/ Accepted 17 May 2006

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-1ß (IL-1ß) 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.

* Corresponding author. Mailing address for Zhong Sheng Sun: Department of Pediatrics, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-7189. Fax: (212) 746-4427. E-mail: sunzs{at}psych.ac.cn. Mailing address for Xiaojing Ma: Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-4404. Fax: (212) 746-4427. E-mail: xim2002{at}med.cornell.edu.

Editor: A. D. O'Brien

{dagger} These authors contributed equally to this work.

Infection and Immunity, August 2006, p. 4750-4756, Vol. 74, No. 8
0019-9567/06/$08.00+0     doi:10.1128/IAI.00287-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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