Chronic shift-lag alters the circadian clock of natural killer cells and promotes lung cancer growth in rats

摘要

Prolonged subjection to unstable work or lighting schedules, particularly in rotating shift-workers, is associated with an increase risk of immune-related diseases, including several cancers. Consequences of chronic circadian disruption may also extend to the innate immune system to promote cancer growth, as natural-killer (NK) cell function is modulated by circadian mechanisms and plays a key role in lysis of tumor cells. In order to determine if NK cell function is disrupted by a model of human shift-work and jet-lag, Fischer (344) rats were exposed to either a standard 12:12 light-dark cycle, or a chronic shift-lag paradigm, consisting of ten repeated 6 hour photic advances occurring every 2 days, followed by 5–7 days of constant darkness. This model resulted in considerable circadian disruption as assessed by circadian running wheel activity. NK cells were enriched from control and shifted animals, and gene, protein, and cytolytic activity assays were performed. Chronic shift-lag altered the circadian expression of clock genes, Per2 and Bmal1, and cytolytic factors, perforin and granzyme B, as well as the cytokine, IFNγ. These alterations were correlated with suppressed circadian expression of NK cytolytic activity. Further, chronic shift-lag attenuated NK cell cytolytic activity under stimulated in-vivo conditions, and promoted lung tumor growth, following intravenous injection of MADB106 tumor cells. Together, these findings suggest chronic circadian disruption promotes tumor growth by altering the circadian rhythms of NK cell function.