Role of Proinflammatory Cytokines on Lipopolysaccharide-Induced Phase Shifts in Locomotor Activity Circadian Rhythm

We previously reported that early night peripheral bacterial lipopolysaccharide (LPS) injection produces phase delays in the circadian rhythm of locomotor activity in mice. We now assess the effects of proinflammatory cytokines on circadian physiology, including their role in LPS-induced phase shifts. First, we investigated whether differential systemic induction of classic proinflammatory cytokines could explain the time-specific behavioral effects of peripheral LPS. Induction levels for plasma interleukin (IL)-1 alpha, IL-1 beta, IL-6, or tumor necrosis factor (TNF)-alpha did not differ between animals receiving a LPS challenge in the early day or early night. We next tested the in vivo effects of central proinflammatory cytokines on circadian physiology. We found that intracerebroventricular (i.c.v.) delivery of TNF-alpha or interleukin IL-1 beta induced phase delays on wheel-running activity rhythms. Furthermore, we analyzed if these cytokines mediate the LPS-induced phase shifts and found that i.c.v. administration of soluble TNF-alpha receptor (but not an IL-1 beta antagonistic) prior to LPS stimulation inhibited the phase delays. Our work suggests that the suprachiasmatic nucleus (SCN) responds to central proinflammatory cytokines in vivo, producing phase shifts in locomotor activity rhythms. Moreover, we show that the LPS-induced phase delays are mediated through the action of TNF-alpha at the central level, and that systemic induction of proinflammatory cytokines might be necessary, but not sufficient, for this behavioral outcome. (Author correspondence: dgolombek@unq.edu.ar)