Circulating levels of cytokines and cytokine receptors in normal human pregnancy

Abstract

Cytokines play a significant role in a number of reproductive processes. Increasing evidence suggests that cytokines exert their diverse activities within the context of a “cytokine network”.

The outcome of reproductive processes depends especially on the interplay between cytokines within gestational tissues and at the fetal-maternal interface. A shift in Th1/Th2 balance is observed, and pregnancy has been described as a Th2 phenomenon with increased local production of immunosuppressive cytokines. Alterations of pregnancy result in a distinct immunoregulatory environment in decidua where cytokines, steroid hormones and prostaglandins act in concert to inhibit fetal impairment. Soluble isoforms of specific cytokine receptors may modify cytokine activities. The fact that normal pregnancy is associated with increased production of soluble receptors, is suggestive of they having a role in the immunoregulation of reproduction.

Local changes in immunoregulation, i.e. mechanisms taking place at the fetal-maternal interface, are regarded as the most important for successful reproduction. However, levels of cytokine and soluble cytokine receptors in maternal circulation are also influenced by normal pregnancy and spontaneous delivery at term. In studies performed in Trondheim, we have observed that maternal serum levels of interleukin-1 (IL-1) and interleukin-6 (IL-6) increased in pregnancy. No changes in IL-1 were observed by increased gestational age or by labor, whereas IL-6 levels increased towards term and by delivery. Soluble IL-1 receptor antagonists (IL-1RA) were increased in pregnant women compared to non-pregnant controls, and IL-1RA concentrations were elevated towards term. Similarly, IL-6 receptors (IL-6R) increased with pregnancy, but IL-6R concentrations remained fairly stable throughout pregnancy. Soluble receptors for tumour necrosis factor (TNFR, p55 and p75) were increased with pregnancy and towards term. Only p55 was elevated in association with labor.

Cytokines appear to have a dichotomous function. Each cytokine may have a normal physiological role if expressed in predetermined sites and amounts. However, each cytokine may have a pathophysiological role if expressed in abnormal sites and amounts. Cytokine levels are increased in association with intrauterine infections, probably causing premature deliveries. Furthermore, maternal levels of cytokines and cytokine receptors are influenced by preeclampsia (PE), and fetal growth retardation in PE is correlated with reduced levels of IL-6 in umbilical serum.