Table 1.

Immune-circadian connection: experimental studies

Author	Study design	Major outcome
Haldberg et al. [17]	Susceptibility of mice to Escherichia coli endotoxin-induced lethality	Lethality varied significantly throughout the day, depending on the time when mice were challenged
Hrushesky et al. [18]	Effect of time of TNF-α administration on lethal toxicity in mice	Nine-fold variation of lethality being greatest during night and particularly before awakening
Keller et al. [21]	Splenocytes from mice, isolated at various times of the day, were challenged with LPS	Circadian rhythmicity of TNF-α and IL-6 secretion was found. More than 8% of the peritoneal macrophage transcriptome oscillates in a circadian function autonomically and depends on time of LPS challenge
Silver et al. [22]	Toll-like receptor 9 (TLR9) expressed in peritoneal macrophages were estimated for circadian rhythmicity in a mouse model of sepsis	Vaccination with TLR9 ligand as adjuvant at the time of enhanced TLR9 responsiveness induced an improved adaptive immune response many weeks later. Moreover, disease severity was dependent on the timing of sepsis induction, coinciding with daily changes in TLR9 expression
Kwak et al. [24]	Study of the long-term effects of INF-γ on SCN neurons by treating dispersed rat SCN neurons with INF-γ for a 4-week period	Firing of SCN neurons and rhythmic expression of clock gene Per1 exhibited a lower average spiking frequency with reduced amplitude and an irregular firing pattern, in relation with controls
Okada et al. [25]	LPS effects on mRNA expression of clock genes in rats	mRNA expression levels of different clock genes, such as Per 1 and Per 2, both in the liver and SCN neurons on day 1, were suppressed with an expression nadir between 10 and 14 h post-challenge. Subsequently, recovery was noted on day 2, whereas controls exhibited a robust circadian profile
Boivin et al. [26]	Estimation of clock gene oscillations in human blood mononuclear cells derived from three human volunteers	Presence of circadian oscillations of Per 1and Per 2 genes
Haimovich et al. [27]	Assessment of clock gene alterations upon LPS administration in peripheral human blood leucocytes, after challenging them with in vivo endotoxin or saline, either at 09:00 a.m or 09:00 p.m.	LPS induced a profound suppression of all clock gene expression by 80% to 90%, between 13 and 17 h post-perfusion, whereas IL-6 and TNF-α returned to baseline within 6 h. However, melatonin and cortisol circadian rhythms were not affected by LPS challenge
Pontes et al. [32]	Colostrum samples for measuring tumor necrosis factor α (TNF-α) and melatonin content were collected from 18 normal delivered mothers in the morning, and diurnal and nocturnal melatonin levels in colostrum from healthy puerperae and mothers with mastitis were compared	Suppression of nocturnal melatonin rise in mothers with mastitis was highly correlated with increased tumor necrosis factor α secretion.
		On the other hand, stimulated, but not quiescent, immune-competent cells secreted in the colostrum produced melatonin in vitro. In addition, this production ceased after bacteria killing
Cruz-Machado et al. [33]	Effects of LPS on melatonin production in rat pineal cultures	Shutdown of melatonin production through TNF-α induction of NF-kB in pineal microglial cells