Placental Ras Regulates Inflammation Associated with Maternal Obesity
Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-01-01
|
| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2018/3645386 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849387238011437056 |
|---|---|
| author | Stella Liong Gillian Barker Martha Lappas |
| author_facet | Stella Liong Gillian Barker Martha Lappas |
| author_sort | Stella Liong |
| collection | DOAJ |
| description | Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity. To determine the effect of Ras on inflammation induced by bacterial endotoxin LPS and proinflammatory cytokines TNF-α or IL-1β, the chemical inhibitor lonafarnib (total Ras inhibitor) and siRNA (siKRAS and siHRAS) were used. Total Ras protein expression together with combined K-Ras and H-Ras activity was significantly increased in the placenta of obese pregnant women and when stimulated with LPS, IL-1β, or TNF-α. Lonafarnib significantly suppressed LPS-, IL-1β-, or TNF-α-induced IL-6, IL-8, MCP-1, and GRO-α expression and secretion in placental tissue. Primary trophoblast cells transfected with siKRAS or siHRAS demonstrated only K-Ras silencing significantly decreased IL-1β-, TNF-α-, or LPS-induced IL-6, IL-8, and MCP-1 expression and secretion. Furthermore, siKRAS significantly reduced downstream ERK-1/2 activation induced by LPS. In trophoblast cells, ERK-1/2 signalling is required for IL-6, IL-8, MCP-1, and GRO-α secretion. These studies implicate a role for K-Ras in regulating inflammation in human placenta. Suppressing overactive placental K-Ras function may prevent adverse fetal outcomes complicated by maternal obesity. |
| format | Article |
| id | doaj-art-2d295bac08cb4bbf9f3aa9b5a116f9be |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-2d295bac08cb4bbf9f3aa9b5a116f9be2025-08-20T03:55:17ZengWileyMediators of Inflammation0962-93511466-18612018-01-01201810.1155/2018/36453863645386Placental Ras Regulates Inflammation Associated with Maternal ObesityStella Liong0Gillian Barker1Martha Lappas2Obstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, AustraliaObstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, AustraliaObstetrics, Nutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, AustraliaHeightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity. To determine the effect of Ras on inflammation induced by bacterial endotoxin LPS and proinflammatory cytokines TNF-α or IL-1β, the chemical inhibitor lonafarnib (total Ras inhibitor) and siRNA (siKRAS and siHRAS) were used. Total Ras protein expression together with combined K-Ras and H-Ras activity was significantly increased in the placenta of obese pregnant women and when stimulated with LPS, IL-1β, or TNF-α. Lonafarnib significantly suppressed LPS-, IL-1β-, or TNF-α-induced IL-6, IL-8, MCP-1, and GRO-α expression and secretion in placental tissue. Primary trophoblast cells transfected with siKRAS or siHRAS demonstrated only K-Ras silencing significantly decreased IL-1β-, TNF-α-, or LPS-induced IL-6, IL-8, and MCP-1 expression and secretion. Furthermore, siKRAS significantly reduced downstream ERK-1/2 activation induced by LPS. In trophoblast cells, ERK-1/2 signalling is required for IL-6, IL-8, MCP-1, and GRO-α secretion. These studies implicate a role for K-Ras in regulating inflammation in human placenta. Suppressing overactive placental K-Ras function may prevent adverse fetal outcomes complicated by maternal obesity.http://dx.doi.org/10.1155/2018/3645386 |
| spellingShingle | Stella Liong Gillian Barker Martha Lappas Placental Ras Regulates Inflammation Associated with Maternal Obesity Mediators of Inflammation |
| title | Placental Ras Regulates Inflammation Associated with Maternal Obesity |
| title_full | Placental Ras Regulates Inflammation Associated with Maternal Obesity |
| title_fullStr | Placental Ras Regulates Inflammation Associated with Maternal Obesity |
| title_full_unstemmed | Placental Ras Regulates Inflammation Associated with Maternal Obesity |
| title_short | Placental Ras Regulates Inflammation Associated with Maternal Obesity |
| title_sort | placental ras regulates inflammation associated with maternal obesity |
| url | http://dx.doi.org/10.1155/2018/3645386 |
| work_keys_str_mv | AT stellaliong placentalrasregulatesinflammationassociatedwithmaternalobesity AT gillianbarker placentalrasregulatesinflammationassociatedwithmaternalobesity AT marthalappas placentalrasregulatesinflammationassociatedwithmaternalobesity |