scholarly journals The p38 Mitogen-Activated Protein Kinase Regulates 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) Expression in Human Trophoblast Cells through Modulation of 11β-HSD2 Messenger Ribonucleic Acid Stability

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4278-4286 ◽  
Author(s):  
Anju Sharma ◽  
Haiyan Guan ◽  
Kaiping Yang
Keyword(s):  
P38 Mapk ◽  
Hydroxysteroid Dehydrogenase ◽  
Mitogen Activated Protein Kinase ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Messenger Ribonucleic Acid ◽  
Mitogen Activated Protein ◽  
Important Regulator ◽  
Interfering Rna

Abstract The placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene) has emerged as a key player in controlling fetal development, but its regulation is incompletely understood. Here we identified p38 MAPK as an important regulator of placental 11β-HSD2. We showed that inhibition of p38 MAPK with the pharmacological inhibitor SB202190 led to an approximately 50% reduction in 11β-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. Furthermore, the effect of SB202190 was confirmed by the use of two additional p38 inhibitors, SB203580 and SB220025. In addition, SB202190 decreased the half-life of 11β-HSD2 mRNA without altering the HSD11B2 promoter activity, indicating that p38 MAPK regulates placental 11β-HSD2 expression through modulation of 11β-HSD2 mRNA stability. Importantly, small interfering RNA-mediated knockdown of p38α caused a 50% reduction in 11β-HSD2 activity, suggesting that p38α is the primary p38 isoform involved. Taken together, these findings suggest a novel pathway controlling placental 11β-HSD2 expression resulting from the activation of p38 MAPK. Given that p38α is abundantly expressed in the human placenta in which its function is largely unknown, our present study also reveals 11β-HSD2 as an important target through which p38α may regulate human placental function and consequently fetal growth and development.

scholarly journals p38 MAPK α and β isoforms differentially regulate plasma membrane localization of MRP2

2016 ◽  
Vol 310 (11) ◽  
pp. G999-G1005 ◽  
Author(s):  
Christopher M. Schonhoff ◽  
Se Won Park ◽  
Cynthia R.L. Webster ◽  
M. Sawkat Anwer
Keyword(s):  
Plasma Membrane ◽  
P38 Mapk ◽  
Hepatoma Cell ◽  
Sodium Taurocholate ◽  
Mitogen Activated Protein Kinase ◽  
Hepatoma Cell Line ◽  
Mitogen Activated Protein ◽  
P38α Mapk ◽  
Opposing Effects ◽  
Interfering Rna

In hepatocytes, cAMP both activates p38 mitogen-activated protein kinase (MAPK) and increases the amount of multidrug resistance-associated protein-2 (MRP2) in the plasma membrane (PM-MRP2). Paradoxically, taurolithocholate (TLC) activates p38 MAPK but decreases PM-MRP2 in hepatocytes. These opposing effects of cAMP and TLC could be mediated via different p38 MAPK isoforms (α and β) that are activated differentially by upstream kinases (MKK3, MKK4, and MKK6). Thus we tested the hypothesis that p38α MAPK and p38β MAPK mediate increases and decreases in PM-MRP2 by cAMP and TLC, respectively. Studies were conducted in hepatocytes isolated from C57BL/6 wild-type (WT) and MKK3-knockout (MKK3−/−) mice and in a hepatoma cell line (HuH7) that overexpresses sodium-taurocholate cotransporting polypeptide (NTCP) (HuH-NTCP). Cyclic AMP activated MKK3, p38 MAPK, and p38α MAPK and increased PM-MRP2 in WT hepatocytes, but failed to activate p38α MAPK or increase PM-MRP2 in MKK3−/− hepatocytes. In contrast to cAMP, TLC activated total p38 MAPK but decreased PM-MRP2, and did not activate MKK3 or p38α MAPK in WT hepatocytes. In MKK3−/− hepatocytes, TLC still decreased PM-MRP2 and activated p38 MAPK, indicating that these effects are not MKK3-dependent. Additionally, TLC activated MKK6 in MKK3−/− hepatocytes, and small interfering RNA knockdown of p38β MAPK abrogated TLC-mediated decreases in PM-MRP2 in HuH-NTCP cells. Taken together, these results suggest that p38α MAPK facilitates plasma membrane insertion of MRP2 by cAMP, whereas p38β MAPK mediates retrieval of PM-MRP2 by TLC.

scholarly journals JNK and p38 Mitogen-Activated Protein Kinase Pathways Contribute to Porcine Circovirus Type 2 Infection

2009 ◽  
Vol 83 (12) ◽  
pp. 6039-6047 ◽  
Author(s):  
Li Wei ◽  
Zhongwu Zhu ◽  
Jing Wang ◽  
Jue Liu
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Porcine Circovirus Type ◽  
Mitogen Activated Protein Kinase ◽  
Porcine Circovirus ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Pcv2 Replication ◽  
Specific Inhibitors

ABSTRACT Infection with a wide variety of viruses often perturbs host cell signaling pathways including the Jun NH2-terminal kinase/stress-activated kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase (p38/MAPK), which are important components of cellular signal transduction pathways. The present study demonstrated for the first time that porcine circovirus type 2 (PCV2), which is the primary causative agent of an emerging swine disease, postweaning multisystemic wasting syndrome, can activate JNK1/2 and p38 MAPK pathways in PCV2-infected PK15 cells. However, PCV2 at an early stage of infection, as well as UV-irradiated PCV2, failed to activate these two MAPK families, which demonstrated that PCV2 replication was necessary for their activation. We further found that PCV2 activated the phosphorylation of JNK1/2 and p38 MAPK downstream targets c-Jun and ATF-2 with virus replication in the cultured cells. The roles of these kinases in PCV2 infection were further evaluated using specific inhibitors: the JNK inhibitor 1 for JNK1/2 and SB202190 for p38. Inhibition of JNK1/2 and p38 kinases by these specific inhibitors did result in significant reduction of PCV2 viral mRNA transcription and protein synthesis, viral progeny release, and blockage of PCV2-induced apoptotic caspase-3 activation in the infected cells. Taken together, these data suggest that JNK/SAPK and p38 MAPK pathways play important roles in the PCV2 replication and contribute to virus-mediated changes in host cells.

scholarly journals Peroxisome Proliferator-Activated Receptor δ Suppresses 11β-Hydroxysteroid Dehydrogenase Type 2 Gene Expression in Human Placental Trophoblast Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1482-1490 ◽  
Author(s):  
Laura Julan ◽  
Haiyan Guan ◽  
Jonathan P. van Beek ◽  
Kaiping Yang
Keyword(s):  
Gene Expression ◽  
Promoter Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Trophoblast Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Human Trophoblast ◽  
Placental Function ◽  
Human Trophoblast Cells

Accumulating evidence suggests that the human placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays a key role in fetal development by controlling fetal exposure to maternal glucocorticoids. Recently, the nuclear peroxisome proliferator-activated receptor δ (PPARδ) has been found to be the most abundantly expressed PPAR subtype in the human placenta, but its function in this organ is unknown. Given that PPARδ-null mice exhibited placental defects and consequent intrauterine growth restriction, the present study was undertaken to examine the hypothesis that PPARδ regulates human placental function in part by targeting 11β-HSD2. Using cultured human trophoblast cells as a model system, we demonstrated that 1) the putative PPARδ agonist carbaprostacyclin (cPGI2) reduced 11β-HSD2 activity as well as 11β-HSD2 expression at both protein and mRNA levels; 2) GW610742 (a selective PPARδ agonist) mimicked the effect of cPGI2, whereas indomethacin (a known ligand for PPARα and PPARγ) had no effect; 3) the cPGI2-induced down-regulation of 11β-HSD2 mRNA did not require de novo protein synthesis; 4) cPGI2 suppressed HSD11B2 promoter activity, but did not alter the half-life of 11β-HSD2 mRNA; and 5) the inhibitory effect of cPGI2 on HSD11B2 promoter activity was abrogated in trophoblast cells cotransfected with a dominant negative PPARδ mutant. Taken together, these findings suggest that activation of PPARδ down-regulates HSD11B2 gene expression in human trophoblast cells, and that this effect is mediated primarily at the transcriptional level. Thus, the present study reveals 11β-HSD2 as an additional target for PPARδ and identifies a molecular mechanism by which this nuclear receptor may regulate human placental function.

Cadmium reduces 11β-hydroxysteroid dehydrogenase type 2 activity and expression in human placental trophoblast cells

2006 ◽  
Vol 290 (1) ◽  
pp. E135-E142 ◽  
Author(s):  
Kaiping Yang ◽  
Laura Julan ◽  
Fran Rubio ◽  
Anju Sharma ◽  
Haiyan Guan
Keyword(s):  
Gene Transcription ◽  
Fetal Growth ◽  
Hydroxysteroid Dehydrogenase ◽  
Environmental Pollutant ◽  
Cadmium Exposure ◽  
Major Constituent ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
Wide Range

Cadmium, a common environmental pollutant and a major constituent of tobacco smoke, has been identified as a new class of endocrine disruptors with a wide range of detrimental effects on mammalian reproduction. During human pregnancy, maternal cadmium exposure, via the environment and/or cigarette smoking, leads to fetal growth restriction (FGR), but the underlying mechanisms are unknown. Although a substantial amount of evidence suggests that cadmium may affect fetal growth indirectly via the placenta, the molecular targets remain to be identified. Given that reduced placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2, encoded by HSD11B2 gene) is causally linked to FGR, the present study was undertaken to examine the hypothesis that cadmium induces FGR in part by targeting placental HSD11B2. Using cultured human trophoblast cells as a model system, we showed that cadmium exposure resulted in a time- and concentration-dependent decrease in 11β-HSD2 activity, such that an 80% reduction was observed after 24-h treatment at 1 μM. It also led to a similar decrease in levels of 11β-HSD2 protein and mRNA, suggesting that cadmium reduced 11β-HSD2 expression. Furthermore, cadmium diminished HSD11B2 promoter activity, indicative of repression of HSD11B2 gene transcription. In addition, the effect of cadmium was highly specific, in that other divalent metals (Zn2+, Mg2+, and Mn2+) as well as nicotine and cotinine (a major metabolite of nicotine) did not alter 11β-HSD2 activity. Taken together, these findings demonstrate that cadmium reduces human placental 11β-HSD2 expression and activity by suppressing HSD11B2 gene transcription. Thus the present study identifies placental 11β-HSD2 as a novel molecular target of cadmium. It also reveals a molecular mechanism by which this endocrine disruptor may affect human placental function and, consequently, fetal growth and development.

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