Corticotropin-releasing hormone, its binding protein and receptors in human cervical tissue at preterm and term labor in comparison to non-pregnant state

Birgitta Byström,Ylva Stjernholm-Vladic,Gunvor Ekman-Ordeberg,Aurelija Klimaviciute,Susanne Abelin-Tornblöm,Jacopo Calciolari,Emma Bertucci,Felice Petraglia

doi:10.1186/1477-7827-4-29

Birgitta Byström, Ylva Stjernholm-Vladic + Show 6 more

Open Access

https://doi.org/10.1186/1477-7827-4-29

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Abstract

BackgroundPreterm birth is still the leading cause of neonatal morbidity and mortality. The level of corticotropin-releasing hormone (CRH) is known to be significantly elevated in the maternal plasma at preterm birth. Although, CRH, CRH-binding protein (CRH-BP), CRH-receptor 1 (CRH-R1) and CRH-R2 have been identified both at mRNA and protein level in human placenta, deciduas, fetal membranes, endometrium and myometrium, no corresponding information is yet available on cervix. Thus, the aim of this study was to compare the levels of the mRNA species coding for CRH, CRH-BP, CRH-R1 and CRH-R2 in human cervical tissue and myometrium at preterm and term labor and not in labor as well as in the non-pregnant state, and to localize the corresponding proteins employing immunohistochemical analysis.MethodsCervical, isthmic and fundal (from non-pregnant subjects only) biopsies were taken from 67 women. Subjects were divided in 5 groups: preterm labor (14), preterm not in labor (7), term labor (18), term not in labor (21) and non-pregnant (7). Real-time RT-PCR was employed for quantification of mRNA levels and the corresponding proteins were localized by immunohistochemical analysis.ResultsThe levels of CRH-BP, CRH-R1 and CRH-R2 mRNA in the pregnant tissues were lower than those in non-pregnant subjects. No significant differences were observed between preterm and term groups. CRH-BP and CRH-R2 mRNA and the corresponding proteins were present at lower levels in the laboring cervix than in the non-laboring cervix, irrespective of gestational age. In most of the samples, with the exception of four myometrial biopsies the level of CRH mRNA was below the limit of detection. All of these proteins could be detected and localized in the cervix and the myometrium by immunohistochemical analysis.ConclusionExpression of CRH-BP, CRH-R1 and CRH-R2 in uterine tissues is down-regulated during pregnancy. The most pronounced down-regulation of CRH-BP and CRH-R2 occurred in laboring cervix, irrespective the length of gestation. The detection of substantial expression of the CRH and its receptor proteins, as well as receptor mRNA in the cervix suggests that the cervix may be a target for CRH action. Further studies are required to elucidate the role of CRH in cervical ripening.

Highlights

Preterm birth is still the leading cause of neonatal morbidity and mortality
corticotropin-releasing hormone (CRH)-BP there were no significant differences in the levels of CRH-binding protein (CRH-BP) mRNA levels between preterm and term respective groups, we did observe a tendency towards a higher level in the non-pregnant than in the pregnant cervix (Figure 1A)
Significantly lower levels of CRH-BP mRNA were seen in the laboring cervix compared to the cervix not in labor at term (p < 0.001)

Summary

Introduction

Preterm birth is still the leading cause of neonatal morbidity and mortality. Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality. Cytokines and several other mediators, including estrogen, progesterone, nitric oxide and prostaglandins, participate in the remodeling of extracellular matrix and ripening of the human cervix [1,7,8,9]. This process can be regarded as an inflammatory reaction associated with elevated levels of cytokines at the time of both preterm and time labor [10,11,12]

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