Cervical Ripening and Parturition in Cows are Driven by a Cascade of Pro‐Inflammatory Cytokines

Abstract

The final stages of cervical ripening and parturition resemble an inflammatory process. Although the role of cytokines in both spontaneous and experimentally induced parturitions has been described in several small laboratory animals and humans, the involvement of pro-inflammatory and regulatory cytokines in physiologic parturition in cows has not been determined. In this study, the cytokine expression profiles were assessed in bovine cervical tissue at several stages of pregnancy and at parturition. Serial biopsy samples of the cervix were obtained from 10 cows on day 185 and day 275 of pregnancy (which was on average 5.4 days before parturition) and at parturition. Messenger RNA expression levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10 and tumour necrosis factor (TNF)alpha were determined using real-time polymerase chain reaction and the number of neutrophils and eosinophils was estimated by Luna and Sirius Red staining. At parturition, IL-8 expression had increased 430-fold (p < 0.001) when compared with that of the day 185 of pregnancy, large numbers of neutrophils had invaded the cervix while eosinophils remained scarce, IL-1beta had increased eightfold (p < 0.05) and IL-6 had not changed significantly. Additionally, IL-10 was increased by 10-fold (p < 0.001) and TNFalpha decreased by 57% (p < 0.05) when compared with that of the day 185 of pregnancy. The large increase in expression of IL-8, enabling the influx of neutrophils, is indicative of its important role in the final stage of cervical ripening and at parturition. As previous studies have shown that neutrophils excrete matrix metalloproteinases (MMP), this might contribute to softening of the cervix. In contrast, the only slightly increased levels of IL-1, steady concentrations of IL-6 and decreased TNFalpha, the potential consequences of increased IL-10 expression, indicate that final cervical of cows in ripening at term parturition is an inflammatory process influenced by regulatory cytokines.

Immunolocalization of Adipocytes and Prostaglandin E2 and Its Four Receptor Proteins EP1, EP2, EP3, and EP4 in the Caprine Cervix During Spontaneous Term Labor1

“…In the intrapartum process, one of the major changes in the uterine cervix involves the degradation of the rigid collagen structure by collagenases and elastases from the polymorphonuclear cells' granules, which is necessary for leading to its softening, effacement, and dilation in the complete ripening cervix [2], independent of uterine contraction [3]. Moreover, the intrapartum process is also correlated with an inflammatory reaction, for example, tissue edema, infiltration of inflammatory cells, and involvement of inflammatory mediators [4][5][6][7], including locally released prostaglandins (PGs) [8].…”

Temporal changes in circulating levels of plasma interleukin-8 during peripartum period in Murrah buffaloes (Bubalus bubalis) under subtropical climate

“…These changes have also been shown to be associated with the increased mRNA expression of IL-8 in maternal circulating leukocytes during term and preterm labor (van Engelen et al 2009;Yuan et al 2009). IL-8 mRNA expression in bovine cervical tissue increased significantly (P<0.001) by about 430-folds during parturition as compared to that on days 185 and 275 of pregnancy which was on average 5.4 days before parturition (van Engelen et al 2009). It also potentiates the effect of IL-1-induced human myometrial contraction through prostaglandin-E 2 (PGE 2 ) production at the time of parturition and upregulates transforming growth factor-beta receptor expression in human myometrium suggesting an additional autocrine-signaling pathway of its action during parturition (Breuiller-Fouche and Germain 2006).…”

“…Such an increase in proteolytic enzymes is suggested to accelerate the separation of fetal cotyledons from maternal caruncles (Kimura et al 2002). These changes have also been shown to be associated with the increased mRNA expression of IL-8 in maternal circulating leukocytes during term and preterm labor (van Engelen et al 2009;Yuan et al 2009). IL-8 mRNA expression in bovine cervical tissue increased significantly (P<0.001) by about 430-folds during parturition as compared to that on days 185 and 275 of pregnancy which was on average 5.4 days before parturition (van Engelen et al 2009).…”

“…Specific reasons for the high IL-8 levels at parturition and postpartum stages are attributed to the roles of IL-8 in cervical ripening to facilitate parturition (Kimura et al 2002;Read et al 2007;Chapwanya et al 2009;Yuan et al 2009;van Engelen et al 2009). Near parturition, leukocytes proliferate in bone marrow before circulating in blood and infiltrating the uterus, or they may proliferate within the uterine tissues, leave the uterus via draining blood or lymph vessels and re-enter the blood stream in increased numbers (Yuan et al 2009).…”

“…Parturition is an inflammatory response and the peripartum period is associated with significant increases in various cytokines and their mRNA expression in various reproductive tissues, maternal circulation, and mammary gland tissues (Chapwanya et al 2009;van Engelen, et al 2009;Bruno et al 2010). During major part of pregnancy, the immune system remains suppressed in order to prevent premature rejection of fetus by the maternal system; however, significant changes occur during term pregnancy and peripartum period, when there is massive invasion of leukocytes in the cervix and uterus to help them ripen (Read et al 2007;Word et al 2007;Yuan et al 2009;van Engelen et al 2008).…”