Peripheral Neuroimmunoendocrine Interactions: Contribution of TNFRp55 to the Circadian Synchronization of Progesterone and Cytokine Production in Joints of Mice in Late Pregnancy

Objective: Circadian rhythms are generated by the suprachiasmatic nucleus of the hypothalamus and involve rhythmic expression of clock genes and proteins. This rhythmicity is transferred to peripheral tissues by neural and hormonal signals. Late pregnancy is considered a state of inflammation which impacts on peripheral tissues such as joints. Tumor necrosis factor (TNF) mediates inflammatory and circadian responses through its p55 receptor (TNFRp55). Neuroimmunoendocrine interactions in joints have not been studied completely. The purpose of this study was to analyze these interactions, investigating the circadian rhythms of progesterone (Pg) and pro- and anti-inflammatory cytokines in the joints at the end of pregnancy (gestational day 18). Moreover, the impact of TNFRp55 deficiency on these temporal oscillations was explored.

Methods: Wild-type and TNFRp55-deficient (KO) C57BL/6 mice were kept under constant darkness in order to study their endogenous circadian rhythms. The expression of the clock genes Bmal1 and Per1 at circadian time 7 was studied by reverse transcription polymerase chain reaction in the ankle joints of nonpregnant and pregnant (gestational day 18) mice. In late pregnancy, Pg and the cytokines interleukin 17 (IL-17), IL-6, and IL-10 were measured in the joints throughout a 24-h period by radioimmunoassay and enzyme-linked immunosorbent assay, respectively.

Results: A significant increase in Bmal1 and Per1 mRNA expression was detected in the joints of pregnant KO mice. Furthermore, KO mice displayed a desynchronization of articular Pg and cytokine production.

Conclusions: Our results show that TNF, via TNFRp55 signaling, modulates articular Pg and cytokine circadian rhythms in late pregnancy. These findings suggest a temporal neuroimmunoendocrine association in peripheral tissues in late pregnancy.