Circadian neuroimmune connections imply a very important feedback component provided by the immune cells to the brain. Indeed, there are several mechanisms by which the immune system can modify central clock structures (Dantzer 2001; Johnson 2002; Larson 2002). Peripheral inflammation results in production of cytokines, which can signal the SCN. In the case of rheumatoid arthritis, inflammation is characterized by increased local synovial and systemic levels of the proinflammatory cytokines IL-1, IL-6, IFN, and TNF-a, which are directly involved in disease's pathophysiology (Feldmann, Brennan, Foxwell, and Maini 2001). Such increased cytokine production plays a key role in neuroendocrine activation pathways in arthritis (Cardinali and Esquifino 2003). As large, hydrophilic proteins, cytokines can only cross the blood-brain barrier at leaky points (the circumventricular organs) or via specific active transport mechanisms (Kastin, Pan, Maness, and Banks 1999). Cytokines act at the level of the organum vasculosum laminae terminalis, a circumventricular organ located at the anterior wall of the third ventricle. IL-1 binds to cells located on the vascular side of this circumventricular structure, thereby inducing synthesis and release of second messenger systems, such as the nitric oxide (NO) synthase/NO and the cyclooxygenase/prostaglandin systems (McCann, Kimura, Karanth, Yu, and Rettori 2002). It must be noted that a central compartment for cytokines exists and that there are data indicating that an increase in peripheral cytokines can evoke a mirror increase in brain levels of cytokines (for ref. see Dantzer 2001). Inflammatory stimuli can also induce CNS stress response through afferent peripheral neural signaling. This was shown mainly for cytokines from the peritoneum that can cause early rapid activation of the nucleus of tractus solitarius in the brainstem via the vagus nerve (Bluthe et al. 1994). Experimental evidence suggests that symptomatology after antigen administration, like anorexia and depressed activity, is a part of a defense response to antigenic challenge and is mediated by the neural effects of cytokines. These changes are known generally as "sickness behavior," that is, the "nonspecific" symptoms (anorexia, depressed activity, loss of interest in usual activities, disappearance of body care activities) that accompany the response to infection. These "nonspecific" symptoms of infection include fever and profound psychological and behavioral changes, among them in their circadian structure (Johnson 2002). Sick individuals experience weakness, malaise, listlessness, and inability to concentrate (Larson 2002). They consistently show indication of decreased amplitude of circadian rhythmicity, like superficial sleep at night and hypersomnia, loss of interest and depressed activity during the day.
One of the most studied physiological roles of immune variables in the central nervous system is the regulation of sleep by pro and anti-inflammatory cytokines. It is now clear that proinflammatory cytokines induce sleep while anti-inflammatory cytokines prevent sleep induction (Majde and Krueger 2005; Obal and Krueger 2005). LPS injections produce similar results to those of the proinflammatory cytokines on sleep regulation and exert differential effects on EEG activity in rats depending on the time of administration (Lancel, Mathias, Faulhaber, and Schiffelholz 1996). Although there is a substantial amount of information regarding the circadian modulation of many immunological variables, there are relatively few data about the possible effect of immune factors on the circadian system itself. Several reports suggest a possible immune feedback regulation of the circadian clock. For example, immunosuppressant drugs such as cyclosporin A affect the phase of locomotor activity (Marpegan et al. 2004) and of hormone secretion (Esquifino, Selgas, Vara, Arce, and Cardinali 1999b; Selgas, Pazo, Arce, Esquifino, and Cardinali 1998) in laboratory animals. Moreover, immune-related transcription factors are present and active in the SCN and its activity is partially necessary for light-induced phase shifts (Marpegan et al. 2004).
Introduction of gram-negative bacteria into the body causes the liberation of toxic, soluble products of the bacterial cell wall, such as LPS, also known as endotoxin. Peripheral administration of LPS exerts profound effects on the sleep-wake cycle and sleep architecture and may produce, at higher doses, fever and a characteristic "sickness behavior" observed during inflammatory diseases, including sleep pattern changes and fever oscillations along the day (Krueger, Obal, Fang, Kubota, and Taishi 2001). In mice, susceptibility to lethal doses of endotoxin increase dramatically during the resting period (Halberg, Johnson, Brown, and Bittner 1960) and a similar temporal pattern of induced mortality has also been established for tumor necrosis factor a (TNF-a) (Hrushesky, Langevin, Kim, and Wood 1994).
Results in hamsters indicate that LPS treatment induces changes in the phase of locomotor activity rhythms in a manner similar to light-induced phase delays (Marpegan, Bekinschtein, Costas, and Golombek 2005). The phase-shifting response to LPS was reduced when the activation of NF-kB, a transcription factor reported to play a role in the photic input of the circadian system (Marpegan et al. 2004), was prevented by sulfasalazine. LPS treatment stimulates the dorsal area of the SCN as assessed by c-Fos activation (Marpegan et al. 2005). Data from our laboratory indicate that melatonin, administered in the drinking water, has the capacity to counteract the effect of LPS on body temperature in hamsters, when injected at "Zeitgeber" time (ZT) 0 (ZT12 defined as the time of light off) (Bruno, Scacchi, Pérez Lloret, Esquifino, Cardinali, and Cutrera 2005). Evidence that melatonin improves survival from endotoxin shock has also been published (Crespo et al. 1999; Maestroni 1996; Wu, Chiao, Hsiao, Chen, and Yen 2001).
Therefore, one possible mechanism through which infection-related changes in circadian rhythms can occur is by modifying directly the activity of cells in the SCN. Cytokine receptors, e.g., IFN-y receptors, have been detected in neuronal elements of ventrolateral SCN (Lundkvist, Robertson, Mhlanga, Rottenberg, and Kristensson 1998). Expression of SCN IFN-y receptors followed a 24-h rhythm, coinciding with the expression of janus kinase 1 and 2 as well as the signal transducer and activator of transcription factor 1, the main intracellular signaling pathway for IFN-y. In an ontogenic study, SCN IFN-y receptors were found to reach their adult pattern between postnatal day 11 and 20, at a time when capacity for photic entrainment of the pacemaker became established (Lundkvist, Andersson, Robertson, Rottenberg, and Kristensson 1999). Indeed, high doses of an IFN-y-TNF-a cocktail disrupt electrical activity of SCN neurons (Lundkvist, Hill, and Kristensson 2002).
The capacity of intracerebroventricular administration of IFN-y to modify 24-h wheel running activity was assessed in golden hamsters (Boggio et al. 2003). Animals received IFN-y or saline at ZT 6 or ZT 18. Intracerebroventricular administration of IFN-y at ZT 6 produced a significant phase advance in acrophase of rhythm, an effect not seen with injection at ZT 18. IFN-y depressed mesor value of rhythm significantly; the effect was seen both with ZT 6 and ZT 18 injections
(Boggio et al. 2003). IFN-y was very effective to disrupt circadian rhythmicity of pituitary hormone release (Cano, Cardinali, Jimenez, Alvarez, Cutrera, and Esquifino
2005). The results supported the view that the circadian sequels arising during the immune reaction can rely partly on central effects of IFN-y (Boggio et al. 2003). A disruptive effect of systemic administration of IFN-a on the circadian rhythm of locomotor activity, body temperature and clock-gene mRNA expression in SCN has also been documented in mice (Ohdo, Koyanagi, Suyama, Higuchi, and Aramaki 2001). Moreover, LPS incubation modified the circadian arginine-vasopressin release from SCN cultures (Nava, Carta, and Haynes 2000). Motzkus et al. (2002) demonstrated that IL-6-induced murine Perl expression in SCN cell cultures.
In recent years we examined the circadian disruption of hormone release and immune-related mechanisms in several animal models including alcoholism (Jimenez, Cardinali, Alvarez, Fernandez, Boggio, and Esquifino 2005; Jimenez, Cardinali, Cano, Alvarez, Reyes Toso, and Esquifino 2004), calorie restriction (Cano, Cardinali, Fernandez, Reyes Toso, and Esquifino 2006; Chacon, Cano, Jimenez, Cardinali, Marcos, and Esquifino 2004; Chacon, Esquifino, Perello, Cardinali, Spinedi, and Alvarez 2005; Esquifino, Chacon, Cano, Marcos, Cutrera, and Cardinali 2004b), and social isolation (Cano et al. 2006; Esquifino, Alvarez, Cano, Chacon, Reyes Toso, and Cardinali 2004a; Esquifino, Chacon, Jimenez, Reyes Toso, and Cardinali 2004c; Perello, Chacon, Cardinali, Esquifino, and Spinedi
2006). Indeed, severe immune challenges such as animal models of sepsis (Bauhofer, Witte, Celik, Pummer, Lemmer, and Lorenz 2001) or infection with blood-borne parasites such as Trypanosoma cruzi or T. brucei (Bentivoglio, Grassi-Zucconi, Peng, and Kristensson 1994) or HIV-infected animals or patients (Bourin, Mansour, Doinel, Roue, Rouger, and Levi 1993; Vagnucci and Winkelstein 1993) display different levels of circadian disruption, including complete arrhythmicity, suggesting that circadian rhythms can be considered a good quality-of-health indicator.
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