scholarly journals Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System

2015 ◽  
Vol 29 (10) ◽  
pp. 1454-1467 ◽  
Author(s):  
K. Lei ◽  
E. X. Georgiou ◽  
L. Chen ◽  
A. Yulia ◽  
S. R. Sooranna ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Feedback Loop ◽  
Prostaglandin Synthesis ◽  
Activator Protein 1 ◽  
Myometrial Cells ◽  
Activator Protein ◽  
Initial Rise ◽  
Cox 2 ◽  
Mapk Phosphatase ◽  
Rate Limiting

Abstract Progesterone (P4) maintains uterine quiescence during pregnancy and its functional withdrawal is associated with increased prostaglandin synthesis and the onset of labor. In primary human myometrial cells, the glucocorticoid receptor (GR) rather than the P4 receptor mediates P4 antagonism of IL-1β-induced cyclooxygenase-2 (COX-2) expression, the rate-limiting enzyme in prostaglandin synthesis. We now report that P4 also acts via GR to induce MAPK phosphatase (MKP)-1 and knockdown of MKP-1 impairs the ability of P4 to repress IL-1β-dependent COX-2 induction. Microarray analysis revealed that P4 repressed preferentially activator protein-1-responsive genes in response to IL-1β. Consistent with these observations, we found that the ability of P4 to reduce c-Jun activation was lost upon GR as well as MKP-1 knockdown. Interestingly, c-Jun levels in human myometrial cells declined upon GR and MKP-1 knockdown, which suggests the presence of an activator protein-1 feedback loop. This is supported by our observation that c-Jun levels declined after an initial rise in primary myometrial cells treated with phorbol 12-myrisatate 13-acetate, a potent activator of c-Jun N-terminal kinase. Finally, we show that MKP-1 is an intermediate in P4-mediated repression of some but not all IL-1β-responsive genes. For example, P4 repression of IL11 and IRAK3 was maintained upon MKP-1 knockdown. Taken together, the data show that P4 acts via GR to drive MKP-1 expression, which in turn inhibits IL-1β-dependent c-Jun activation and COX-2 expression.

scholarly journals Differential Activation of the Connexin 43 Promoter by Dimers of Activator Protein-1 Transcription Factors in Myometrial Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 2048-2054 ◽  
Author(s):  
Jennifer A. Mitchell ◽  
Stephen J. Lye
Keyword(s):  
Transcription Factors ◽  
Connexin 43 ◽  
Family Members ◽  
Expression Vectors ◽  
Central Component ◽  
Activator Protein 1 ◽  
Cx43 Expression ◽  
Myometrial Cells ◽  
Activator Protein ◽  
Expression Of Genes

Abstract The expression of activator protein-1 (AP-1) transcription factors is increased in the myometrium at term and may therefore regulate the expression of genes, such as connexin 43 (Cx43), required for the onset of labor. The region upstream of the mouse, rat, and human Cx43 genes contains two consensus AP-1 binding sequences, a proximal AP-1, located close to the TATA box, and a distal AP-1, 1 kb upstream. A transient transfection system was developed in which Syrian hamster myometrial cells were transfected with Cx43 promoter-luciferase constructs in combination with expression vectors for the AP-1 family. Transfection with c-Jun or JunB had no effect on transcription from the Cx43 promoter, whereas transfection with JunD or combinations of Jun and Fos family members led to significant increases in transcription. Deletion of the distal AP-1 site did not abrogate transcription driven by Fos/Jun, whereas a 2-bp mutation in the proximal AP-1 site significantly reduced pCx43 transactivation by AP-1 dimers. Dimers comprising Fos/Jun proteins conferred greater transcriptional activity than Jun dimmers, with Fra-2/JunB combination conferring greatest activity. These data suggest that increased expression of Fos family members in the myometrium at term drives the increase in Cx43 transcription and expression during labor. Because expression of Fra-2 increases earlier than other Fos family members and confers the highest transcriptional drive to the Cx43 promoter, our data suggest that Fra-2 is a central component in the regulation of Cx43 expression during labor.

scholarly journals Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes

2017 ◽  
Vol 45 (14) ◽  
pp. 8596-8608 ◽  
Author(s):  
Emily R. Weikum ◽  
Ian Mitchelle S. de Vera ◽  
Jerome C. Nwachukwu ◽  
William H. Hudson ◽  
Kendall W. Nettles ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Activator Protein 1 ◽  
Inflammatory Genes ◽  
Activator Protein ◽  
Recognition Motifs

Mechanical stretch and progesterone differentially regulate activator protein-1 transcription factors in primary rat myometrial smooth muscle cells

2004 ◽  
Vol 287 (3) ◽  
pp. E439-E445 ◽  
Author(s):  
Jennifer A. Mitchell ◽  
Oksana Shynlova ◽  
B. Lowell Langille ◽  
Stephen J. Lye
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Direct Action ◽  
Muscle Cells ◽  
Mechanical Stretch ◽  
Activator Protein 1 ◽  
Static Stretch ◽  
Myometrial Cells ◽  
Activator Protein

During pregnancy, stretch of the uterus, imposed by the growing fetus, is an important signal for the induction of genes involved in the onset of labor. In this study, the expression of activator protein-1 (AP-1) family mRNAs in response to in vitro stretch was investigated in myometrial cells. Rat primary myometrial smooth muscle cells were plated onto collagen I-coated Flex I culture plates and subjected to 25% static stretch on day 4 of culture. Static stretch induced an increase in the expression of c -fos, fosB, fra-1, c -jun, and junB. The expression of both c -fos and junB was maximally induced at 30 min by static stretch. The peak induction for fosB and c -jun occurred at 1 h, whereas the peak of fra-1 induction occurred between 1 and 2 h after application of stretch. Treatment of myometrial cells with progesterone (100 nM, 400 nM, 1 μM) for 1 or 6 h before the application of static stretch did not affect the magnitude of the c -fos response. However, 24 h of progesterone exposure reduced the magnitude of c -fos and fosB stretch induction at both the 400 nM and 1 μM doses. These data indicate that several members of the AP-1 family are stretch-responsive genes in myometrial smooth muscle cells. This response can be attenuated by pretreatment with progesterone; however, the requirement for longer pretreatment times suggests that the inhibitory actions of progesterone do not occur through a direct action of the progesterone receptor within the promoter regions of AP-1 genes.

scholarly journals Progesterone Acts via the Nuclear Glucocorticoid Receptor to Suppress IL-1β-Induced COX-2 Expression in Human Term Myometrial Cells

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e50167 ◽  
Author(s):  
Kaiyu Lei ◽  
Li Chen ◽  
Ektoras X. Georgiou ◽  
Suren R. Sooranna ◽  
Shirin Khanjani ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Myometrial Cells ◽  
Cox 2

scholarly journals Neuromedin B mediates IL-6 and COX-2 expression through NF-κB/P65 and AP-1/C-JUN activation in human primary myometrial cells

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Texuan Zhu ◽  
Jingfei Chen ◽  
Yanhua Zhao ◽  
Jiejie Zhang ◽  
Qiaozhen Peng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nuclear Factor Κb ◽  
Potential Interaction ◽  
Inflammatory Factors ◽  
Activator Protein 1 ◽  
Myometrial Cells ◽  
Neuromedin B ◽  
Cox 2 ◽  
Underlying Mechanisms ◽  
Labor Onset

Abstract Neuromedin B (NMB) and its receptor regulate labor onset by mediating inflammatory factors; however the underlying mechanisms remain poorly understood. The present study is aimed to investigate the mechanisms of NMB-induced cyclo-oxygenase 2 (COX-2) expression and interleukin (IL)-6 generation in human primary myometrial cells. The results indicated that NMB could increase phosphorylation of nuclear factor κB (NF-κB) transcription factor p65 (p65) and Jun proto-oncogene, activator protein 1 (AP-1) transcription factor subunit (c-Jun), and in turn, markedly up-regulated the expression levels of COX-2 and IL-6. This up-regulation was significantly attenuated by knockdown of p65 or c-Jun, and enhanced by overexpression of p65 or c-Jun. Furthermore, we identified a potential interaction between p65 and c-Jun following NMB stimulation. In addition, a significant positive correlation was observed between the amount of phosphorylated p65 and the levels of COX-2 and IL-6, and between the amount of phosphorylated c-Jun and COX-2 and IL-6 levels. These data suggested that NMB-induced COX-2 and IL-6 expression were mediated via p65 and c-Jun activation.

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