Interactions between the circadian and the immune system: a framework for the comprehension of disease

PALADINO N.; LEONE M.J.; CASIRAGHI L.P.; AGOSTINO P.V.; GOLOMBEK D.A.; CHIESA J.J.

Biological Clocks: Effects on Behavior, Health and Outlook

Nova Science Publishers

Año: 2010; p. 121 - 138

Daily environmental changes have imposed a selective pressure for life on Earth, driving the development of a circadian clock mechanism for the generation and entrainment of rhythms in physiological and behavioral variables (e.g. body temperature, hormonal secretion, sleep, locomotor activity, etc.). In mammals, the clock resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts its activity is the light-dark cycle. Indeed, most immune factors and processes are under circadian control, although the efferent pathways that control these cycles are not completely understood. In addition, circadian disorders are usually associated with disease, and temporal disarrangements in immune parameters are closely related to the onset or development of pathological mechanisms. In particular, several lines of evidence link clock activity to cancer disease. Epidemiologic studies show associations between circadian rhythms disruption and cancer risk or inadequate responses to treatment. Moreover, proinflammatory cytokines, some of which have been reported to be key actors in tumour signaling, can generate deep behavioral alterations comprising clock-associated variables during tumor progression, such as altered sleep pattern, fatigue, and lower quality of life. We argue that the circadian-immune interaction operates in two directions: while the SCN (or other, peripheral, clocks) might drive circadian variations in several immune variables, humoral signals can in turn affect the molecular mechanism of the circadian clock and its entrainment. For example, higher diurnal lethality depicts a strong circadian modulation of lipopolysaccharide (LPS)-induced sepsis, which is also observed using TNF-a stimulation. Current clinical data show a strong correlation between time of day and illness manifestation or immune activity. Conversely, administration of subpyrogenic doses of LPS, as well as of proinflammatory cytokines IL-1bƒn and TNF-aƒz induces changes in SCN-driven locomotor activity rhythms. At the molecular level, this effect is achieved through activation of a transcriptional pathway involving nuclear factor-kB (NF-kB). This and other pathways (such as mitogen-activated-kinase (MAPK) signaling), lead to the expression of specific genes of clockwork mechanism, which eventually set its phase and regulates its rhythmic output. Regarding cancer disease, the clock genes Per1 and Per2 are involved in DNA damage response, and could therefore regulate tumour suppression. Moreover, the expression of many cell-cycle genes is under circadian control. In addition, alterations in other components of the molecular clock, as those in members of the casein kinase family, have also been linked to cancer disease. In this review we analyze the interaction between the circadian and immune systems, and explore the signal transduction pathways which could participate in this dialogue. The precise knowledge of this interaction might be extremely useful for the understanding of diseases development such as cancer.