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.