Effect Of PPARα On Maintaining Pregnancy Or Initiating Labor In Human Pregnant Myometrium

BackgroundHuman pregnancy and labor are complex physiological evens. Despite impressive progress in scientific research on reproduction, the mechanisms that maintain pregnancy and initiate labor are not fully understood. Inflammation reactions with the release of cytokines are among the most accepted theories for labor. Although, the role of peroxisome proliferator activated receptor alpha (PPARa) in human parturition remains to be elucidated, PPARa has been demonstrated to exhibit anti-inflammatory activities and therefore, are hypothesized to play a role in labor suppression and maintenance of uterine quiescence.PPARa is a nuclear receptor activated by natural ligands, such as fatty acids, and by synthetic ligands, such as fibrates. PPARa exerts lipid metabolism, fatty acid oxidation, glucose homeostasis and anti-inflammatory effects which may also play a role in pregnancy and parturition. PPARa activation has been reported to induce production of inducible nitric oxide synthase (iNOS), increasing NO levels, and inhibit interleukin-1β(IL-1β) and cyclooxygenase (COX)-2expression, which could maintain uterine quiescence. In the choriodecidua, expression of PPARa declined with the onset of labor in normal pregnancy. Definitive date, however, is lacking with dynamic expression of PPARa in human pregnant smooth muscle cells. The onset of labor requires a switch from the anti-inflammatory uterine state to an active and pro-inflammatory environment. To reveal the biochemical process that switches the myometrium from a quiescence to an active contractive state is very important for understanding the mechanism underlying human labor. ObjectiveThe first purpose of this investigation was to determine the cellular location of PPARa in human myometrium. Having confirmed the presence of PPARa, the next aim of this study was to explore pregnancy-and labor-associated changes of anti-inflammatory PPARa and pro-inflammatory IL-1βin human myometrium and to investigate their roles in maintaining pregnancy or initiating labor. MethodsFor this investigation, human myometrium was obtained from women in the following four groups:non-pregnant (NP)(n=10), preterm not in labor (PNL)(n=10, gestation range20-35weeks), term not in labor (TNL)(n=20, gestation range37-41weeks) and term in labor (TL)(n=20, gestation range37-41weeks). Immunohistochemistry was used to locate and confirm expression of PPARa. Relative quantitative real-time PCR and western blotting were employed to study expressions of anti-inflammatory PPARa and pro-inflammatory Interleukin-1β. Pearson test is used to analyze the correlations between PPARa and IL-1βon mRNA and protein levels.Results1. Immunohistochemistry revealed that PPARa was all identified in non-pregnant, preterm not in labor, term not in labor and term in labor muscle tissues with staining mainly in the uterine SMCs, and to some degree within the endothelial cells of vessels. PPARa staining was primarily located in nuclear.2. Compared to other groups, the mRNA expression of PPARa in group PNL was significantly higher (P<0.01), however the expression in group TL was remarkably lower than NP, PNL and TNL group (P<0.05). The expression of IL-1β mRNA in group PNL was much lower than the other three groups (P<0.01), but when IL-1β mRNA from term labor women were compared to NP, PNL and TNL, significant increasing in mRNA expression was detected. No significant difference could be seen in the comparison of NP with TNL on PPARa and IL-1β mRNA expressions (P>0.05).3. PPARa protein from PNL women revealed significantly higher expression compared to NP, TNL or TL (P<0.01), while the expression in group TL was the lowest among the four groups (P<0.05). However, there was no change in PPARa protein between NP and TNL group (P>0.05). With the growth of gestational age, IL-1βprotein expression was increasing gradually from NP, PNL to TNL women, and the expression in TL was the highest obviously (P<0.01).4. There was significantly negative correlation between PPARa and IL-1βmRNA expression (r=-0.765, P<0.01) and on protein level (r=-0.624, P<0.01). The length of labor and cervical dilatation were significantly correlated with IL-1βprotein (r=0.858, P<0.01; r=0.879, P<0.01).Conclusions1. The expressions of PPARa and IL-1βobviously change in the human pregnant myometrium.2. The increased expression of PPARa expression may be important for mediating anti-inflammatory uterine quiescence and labor suppression during early and mid-trimester pregnancy. Decreased expression of PPARa in uterine with parturition may be important for initiating labor, however there is no difference in the PPARa expression with progressive cervical dilatation and ongoing labor.3. The increased IL-1βis crucial for parturition and the ongoing labor process was significantly correlated with IL-1βprotein. The increased IL-1βprotein was in part synthesized within human myometrium and another part might stem from cytokine influx by circulation during parturition.4. The changes observed suggest that PPARa may play a role to maintain pregnancy or initiate labor through inhibition expression of IL-1βin human myometrium.