Interleukin‐6 Up‐Regulates the Oxytocin Receptor in Cultured Uterine Smooth Muscle Cells

Rauk, Phillip N.; Friebe-Hoffmann, U

doi:10.1111/j.8755-8920.2001.450305.x

Cited by 83 publications

(50 citation statements)

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“…IL-6 promotes synchronous myometrial contraction via PG synthesis and expression of oxytocin and its receptor. [32][33][34][35] Furthermore, IL-6 2/2 mice showed impaired leukocyte accumulation, suggesting that IL-6 also plays a role in leukocyte recruitment. 36 Two CXC family chemokines (CXCL1 and CXCL8) are well known for their strong chemoattractant activity on neutrophils, and their expression in human myometrium during spontaneous labour was reported and confirmed by many research groups.…”

Section: Discussionmentioning

confidence: 99%

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

2014

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Spontaneous term labour is associated with amplified inflammatory events in the myometrium including cytokine production and leukocyte infiltration; however, potential mechanisms regulating such events are not fully understood. We hypothesized that mechanical stretch of the uterine wall by the growing fetus facilitates peripheral leukocyte extravasation into the term myometrium through the release of various cytokines by uterine myocytes. Human myometrial cells (hTERT-HM) were subjected to static mechanical stretch; stretch-conditioned media was collected and analysed using 48-plex Luminex assay and ELISA. Effect of stretch-conditioned media on cell adhesion molecule expression of human uterine microvascular endothelial cells (UtMVEC-Myo) was detected by quantitative polymerase chain reaction (qPCR) and flow cytometry; functional assays testing leukocyte-endothelial interactions: adhesion of leukocytes to endothelial cells and transendothelial migration of calcein-labelled primary human neutrophils as well as migration of THP-1 monocytic cells were assessed by fluorometry. The current in vitro study demonstrated that mechanical stretch (i) directly induces secretion of multiple cytokines and chemokines by hTERT-HM cells (IL-6, CXCL8, CXCL1, migration inhibitory factor (MIF), VEGF, G-CSF, IL-12p70, bFGF and platelet-derived growth factor subunit B (PDGF-bb), P,0.05); stretch-induced cytokines (ii) enhance leukocyte adhesion to the endothelium of the surrounding uterine microvasculature by (iii) inducing the expression of endothelial cell adhesion molecules and (iv) directing the transendothelial migration of peripheral leukocytes. (vi) Chemokine-neutralizing antibodies and broad-spectrum chemokine inhibitor block leukocyte migration. Our data provide a proof of mechanical regulation for leukocyte recruitment from the uterine blood vessels to the myometrium, suggesting a putative mechanism for the leukocyte infiltrate into the uterus during labour and postpartum involution.

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Section: Discussionmentioning

confidence: 99%

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

2014

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“…At term, estrogen and interleukin-6 have been suggested to modulate oxytocin receptor gene expression and both are elevated at the time of parturition (Young et al 1997). Interleukin-1 down-regulates uterine oxytocin receptor in a time-and dose-dependent fashion (Rauk & Friebe-Hoffmann 2000). Regardless of the mechanisms controlling the cardiac oxytocin system, it is interesting to note that inhibited cardiac oxytocin or oxytocin receptors in rat heart at term is consistent with increased heart rate and force of contraction observed in term pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum

Mukaddam‐Daher

Jankowski²,

Wang³

et al. 2002

Journal of Endocrinology

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We have recently uncovered the presence of an oxytocin system in the heart and found that oxytocin is a physiological regulator of atrial natriuretic peptide (ANP), a diuretic, natriuretic and vasodilator cardiac hormone. However, dynamic changes in these systems during gestation, when mechanisms of volume and pressure homeostasis are altered, are not clear. Accordingly, ANP, oxytocin and oxytocin receptors were evaluated in rat hearts and plasma at three stages of gestation (7, 14 and 21 days) and at 2 and 5 days postpartum. Compared with non-pregnant controls, plasma ANP was elevated in midgestation, but significantly decreased at term (21 days), to increase again postpartum. Right and left atrial ANP mRNA levels were not altered throughout gestation but increased by 1·5-to 2-fold postpartum (P<0·01). At term, ANP content in right (8·7 1·2 vs 12·7 1·1 µg/mg protein, P<0·04) and left (3·5 0·6 vs 8·5 2·0 µg/mg protein, P<0·01) atria increased. These findings imply that decreased plasma ANP at term results from inhibition of release rather than decreased synthesis. In parallel, oxytocin, a stimulator of ANP release, decreased in left atria at day 7 to 50% of non-pregnant levels and remained low throughout gestation. Oxytocin receptor mRNA increased in left atria at 7 and 14 days of gestation by 2-and 5-fold respectively, but decreased at 21 days to lower than non-pregnant levels to increase again (3-fold) postpartum. The changes in oxytocin receptor expression at term and postpartum paralleled oxytocin receptor protein determined by Western blot. These results imply that pregnancy is associated with dynamic changes in the cardiac oxytocin system (peptide and/or receptors), which may influence natriuretic peptide release. Together, these peptides would act on their receptors in the heart, vasculature and kidneys to maintain vascular tone and renal function throughout gestation and postpartum.

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“…Based on such comparative analyses as well as the clinical relationship between intrauterine infection and the onset of preterm birth, many investigators hypothesized that OTR transcription would be up-regulated by proinflammatory cytokines such as interleukin (IL)-1 and IL-6 via activation of the binding elements for nuclear factor (NF)-IL-6 or Stat3 (Inoue et al 1994). In cultured uterine smooth muscle cells obtained at Caesarean section, IL-6 up-regulates OTR expression in a tyrosine kinasedependent manner (Rauk et al 2001). However, Schmid et al (2001) reported that both IL-1 and IL-6 down-regulate the transcription of a reporter gene connected to the OTR gene promoter transfected into a human myometrial cell line (ULTR).…”

Section: The Otr Gene and Its Transcriptional Regulationmentioning

confidence: 99%

Molecular regulation of the oxytocin receptor in peripheral organs

Kimura¹,

Saji²,

Nishimori³

et al. 2003

Journal of Molecular Endocrinology

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The oxytocin receptor belongs to the G-protein-coupled seven transmembrane receptor superfamily. Its main physiological role is regulating the contraction of uterine smooth muscle at parturition and the ejection of milk from the lactating breast. Oxytocin receptor expression is observed not only in the myometrium and mammary gland but also in the endometrium, decidua, ovary, testis, epididymis, vas deferens, thymus, heart and kidney, as well as in the brain. The expression profile shows a tissue-specific as well as a stage-specific pattern. The oxytocin receptor gene is a single-copy gene consisting of four exons and three introns, localized at 3p25-3p26·2 in the human chromosome. In transfection studies using a fusion construct containing the promoter region of the oxytocin receptor gene inserted in a reporter plasmid, neither proinflammatory cytokines nor oestrogen directly activate the gene. The nuclear fractions from up-regulated (term myometrium) and down-regulated (non-pregnant myometrium) tissues show differential patterns of protein binding to the 5′-flanking region, and a human homologue of chicken MafF has been cloned as a term-myometrium-specific oxytocin receptor modulator. The oxytocin receptor gene appears to be highly methylated. Methylation around intron 1 and in intron 3 might contribute to tissue-specific suppression of the gene. The oxytocin receptor is also regulated by desensitization, whose mechanism appears to involve loss of ligand-binding activity of the protein as well as suppression of the oxytocin receptor mRNA transcription. These findings taken together indicate that the oxytocin receptor is regulated in a very complicated manner, and the transcriptional regulatory elements critical for this regulation should be investigated further.

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Interleukin‐6 Up‐Regulates the Oxytocin Receptor in Cultured Uterine Smooth Muscle Cells

Abstract: IL-6 up-regulates uterine OTR mRNA expression and binding capacity in cultured human myocytes most likely through tyrosine and serine phosphorylation pathways involving the nuclear factor STAT-3.

Cited by 83 publications

References 0 publications

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

Regulation of cardiac oxytocin system and natriuretic peptide during rat gestation and postpartum

Molecular regulation of the oxytocin receptor in peripheral organs

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