DISCUSSION
PGE2 is known as an important factor that is related to the induction of parturition in cattle [18]. Additionally, our previous studies have shown that PGE2 has suppressive effects on immune responses, particularly those involving Th1 [16, 17]. However, the association of PGE2 induction during parturition with the suppression of immune responses is still unknown. Therefore, in the current study, we examined whether PGE2 was associated with the suppression of immune responses in periparturient period. Our data showed that PGE2 was induced, and that Th1 responses were inhibited before parturition in pregnant cattle. In addition, both BLV-specific and BLV-nonspecific Th1 responses were suppressed before parturition in pregnant cattle infected with BLV. During BLV infection, the suppression of Th1 responses against BLV-antigen is associated with disease progression [25, 26]. In the advanced stages of BLV infection, BLV-specific Th1 responses are downregulated, thus leading to further disease progression and possible EBL [27]. Thus, PGE2 mediated inhibition of BLV-specific Th1 responses around parturition might be a mechanism underlying progression to the clinical stage of BLV infection. In this study, no significant change of BLV proviral load was observed in periparturient period in BLV-infected pregnant cattle (data not shown). However, previous reports have shown that PGE2/EP4 signaling facilitates BLV viral gene transcription via the activation of cyclic-AMP/protein kinase A/cAMP-response element signaling [17, 28]. Thus, additional experiments with larger numbers of BLV-infected pregnant cattle are needed to examine the effect of PGE2 on BLV proviral load during parturition.
In this study, we identified a novel mechanism of PGE2upregulation via estradiol. Previous studies have shown that treatment with estradiol induces NF-κB activation in human and rat models [29, 30]; moreover, NF-κB activation is essential for COX-2 induction [14, 31]. Therefore, estradiol presumably induces PGE2 production in the blood via NF-κB activation. In addition, our data showed that PGE2/EP4 signaling, at least in part, involved in the suppressive effect of estradiol. By contrast, we did not observe a significant difference between the group treated with estradiol alone and the group treated with estradiol after pretreatment with the EP2 antagonist. Generally, EP2 and EP4 are receptors, which are associated with the immunosuppressive activity of PGE2. However, EP4 represents a high-affinity receptor, whereas EP2 requires significantly higher concentrations of PGE2 for effective signaling [15]. Therefore, the differential effects of EP2 and EP4 blockades are presumably due to the affinity of each receptor.
Tregs are critical for maternal tolerance [4]. Several reports have demonstrated that estrogen drives the induction of Tregs in murine models [32, 33]. Additionally, our previous reports showed that PGE2 upregulates the expression levels of Foxp3and TGFβ1 in bovine PBMCs [17] and suppressive function of Tregs is associated the disease progression during BLV infection [34]. Collectively, the available data suggest that during parturition, Tregs induced by the estradiol/PGE2 pathway might suppress Th1 responses and contribute to the progression of BLV infection. Further studies are warranted to investigate the involvement of Tregs in the suppression of Th1 responses during parturition.
Our previous studies have shown that PGE2 upregulation is also involved in the progression of other bovine chronic diseases, such as Mycoplasma bovis infection and Johne’s disease, which is caused by Mycobacterium avium subsp. paratuberculosis[16, 35]. Additionally, in terms of Johne’s disease, it has been reported that the stress related to parturition is a risk factor for eliciting the onset of the clinical stage of the disease [36]. However, no report has been reported whether PGE2induction during parturition inhibits M. bovis -specific andM. avium subsp. paratuberculosis -specific Th1 responses. The involvement of the estradiol/PGE2 pathway in Th1 suppression during parturition should be determined in further experiments by using pregnant cattle with these diseases.
In conclusion, during parturition, BLV-specific Th1 responses are suppressed via estradiol-induced PGE2, which contributes to the disease progression of BLV-infection. Additionally, estradiol-induced PGE2 also inhibited BLV-nonspecific Th1 responses, thus suggesting that PGE2 might be involved in susceptibility to opportunistic infections in the periparturient period. To the best of our knowledge, this is the first study to show the suppressive function of the estradiol/PGE2/EP4 pathway. Further studies will open up new avenues for the control of infections during parturition both in pregnant cattle and in pregnant women.