The multivariate analysis (OPLS-DA) showed no significant separation between morning and evening samples based on the 71 analyzed cytokines/chemokines/growth factors (supplementary Table 3, available at http://links.lww.com/PR9/A48) and we therefore refrained from further conventional statistical analyses (ie, Wilcoxon tests).
Cytokines, chemokines, and growth factors have been linked to different conditions, and some have been shown to be produced and secreted with circadian rhythm. The secretion of proinflammatory cytokines peak (IL-2, IFN-g, TNF-α) during the evening, whereas levels of IL-6 follow a biphasic rhythm.31 Differences in median concentrations for several inflammatory substances could be observed between morning and evening samples, but the differences were not significant (supplementary Table 3, available at http://links.lww.com/PR9/A48). However, the expression level of several proteins changed between morning and evening. Coagulation factor XIII B chain was the highest important protein (VIP = 1.8) that contributed to the discrimination between samples collected during the morning and evening. This protein is involved in the fibrinolysis, and a circadian variation of fibrinolytic system in blood has been reported previously.1 Those authors reported an increase of the fibrinolytic activity in blood at 6 PM. Thus, the increased level of coagulation factor XIII B chain during the evening in this proteomic study is in the line with previously reported study.
Circadian variation of several proteins involved in innate immunity was also detected. Increased (P < 0.05) levels of a number of components of the complement system (complement factor H, C4b-binding protein alpha chain, complement component C8 alpha chain, complement factor H-related protein 1, complement component C7, and C4b-binding protein beta chain), and decreased (P < 0.05) levels of other components (complement C2, complement factor B, complement C5, complement factor I, and complement C3), were found in the evening samples compared with the morning samples. The most important complement proteins for the separation between the groups were complement factor H (VIP = 1.77) and C4b-binding protein alpha chain (VIP = 1.71) whose levels were increased during the evening. It has been found that the immune response is depending on the time of the day.6,17 For example, plasma levels of C3 and C4 are reported to be influenced by the circadian rhythm and sleep. Poor sleep measures have been associated with increased levels of inflammatory complement components.14,28
The authors have no conflict of interest to declare.
The research was financially supported by the Swedish Research Council (K2009-52P-20943-03-2, 2014-2979, 2018-02470), the Stockholm County Council (SOF project), the Swedish Dental Society, ALF grants at Region Östergötland, and AFA Insurance (140341) The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PR9/A48.
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