Chronic Shift-Lag Alters the Circadian Clock of NK Cells and Promotes Lung Cancer Growth in Rats

Abstract

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.

Cardiac Per2 Functions as Novel Link between Fatty Acid Metabolism and Myocardial Inflammation during Ischemia and Reperfusion Injury of the Heart

“…In fact, complete lack of these transcripts in wildtype mice indicate that Per2 is a necessary suppressor. However, if the anti-inflammatory function of Per2 is mediated by its function in the vasculature [59], myocytes or the invading inflammatory cells [60] will require future studies using conditional knockout mouse models.…”

Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans

“…Indeed, studies in rodents and in humans using environmental circadian disruption (e.g., simulated shift work, jetlag, light-dark cycles different from 24 h) associated circadian misalignment with various health consequences (3). For instance, rodents subjected to repeated jetlag exhibit faster tumor growth (4,5) and more severe septic shock in response to endotoxin administration (6). In humans under a 28-h day protocol (forced desynchrony), altered leptin levels, as well as glucose and insulin response after meals (up to a prediabetic level), were observed when the circadian and behavioral cycles were misaligned compared with the days when they were well aligned (7).…”

Effects of Circadian Disruption on Physiology and Pathology: From Bench to Clinic (and Back)

“…In this chronic jet lag the expression of the cytokines IL-1β, IL-10, IL-12, IL-13, GM-CSF, and TNF-α was significantly increased 24 h after LPS injection, and in vitro macrophage stimulation with LPS produced higher levels of IL-6 (Castañon-Cervantes et al 2010). Chronic jet lag also impaired NK cells cytolytic activity, as well as altered rhythms in clock gene and cytokine expression (Logan et al 2012b). Deleterious effects of abnormal entrainment were also reported in a mice model of experimental colitis, where chronic inversions of the LD cycle every 5 days led to increased symptoms as reduced body mass, abnormal intestinal histopathology, and potentiated inflammatory response (Preuss et al 2008).…”