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JNCI Journal of the National Cancer Institute 1988 80(15):1232-1237; doi:10.1093/jnci/80.15.1232
© 1988 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 80, No. 15, 1232-1237, October 5, 1988
© 1988 Oxford University Press

Natural Killer Cell Activity: Age, Estrous-and Circadian-Stage Dependence and Inverse Correlation With Metastatic Potential2

William J. M. Hrushesky3,4,*, Scott A. Gruber4, Robert B. Sothern3, Rosemary A. Hoffman5, David Lakatua4, Ann Carlson4, Frank Cerra4, Richard L. Simmons5

3Department of Medicine, University of Minnesota Hospitals Minneapolis, MN.
4Departments of Laboratory Medicine and Pathology. (W. J. M. Hrushesky, D. Lakatua), Biomedical Engineering (W. J. M. Hrushesky), and Surgery (S. A. Gruber, A. Carlsom, F. Cerra), University of Minnesota Minneapolis, MN.
5Department of Surgery, University of Pittsburgh Pittsburgh, PA 15261

*Correspondence to: Dr. William J. M. Hrushesky, Department of Medicine, Box 414, University of Minnesota Hospital and Clinic, University of Minnesota, Minneapolis, MN 55455.

The timing within the estrous cycle of surgical removal of a transplanted murine mammary tumor profoundly influences the frequency of pulmonary metastases. We investigated the potential role of the immune response in this phenomenon by measuring splenic natural killer (NK) cell activity and interleukin-2 (IL-2) production in syngeneic tumor-free mice of two age groups at each of two circadian times and in each of four estrous stages. Estrous stage was determined by assessment of vaginal smear ceUular-ity immediately prior to killing and spleen harvest. In a single-cell spknocyte preparation, NK cytotoxicity against a standard tumor cell target was assessed using a radiolabeled chromium release assay while IL-2 activity was determined in a bioassay utilizing the IL-2-dependent CTLL-2 cell line. Mice from the younger group were found to have eight-fold higher NK activity and 35% greater IL-2 production. After normalization of NK and IL-2 values for age, a highly statistically significant difference in NK activity was found among the four estrous and between the two circadian stages of sacrifice. NK activity was greater during the daily resting span across every estrous stage. IL-2 values were highest in diestrus and proestrus when sampled in the light span and in estrus-metestrus when sampled in the dark. The stages within the fertility cycle associated with lowest metastatic potential (proestrus/estrus) correspond precisely with those of highest splenocyte NK activity. These results indicate that an important component of the cellular immune response varies rhythmically both during the fertility and circadian cycles of the host The rhythmic changes in NK activity may be in part responsible for the similarly rhythmic frequency of postsurgical metastatic dissemination. [J Natl Cancer Inst 1988;80:1232–1237]



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