Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis
Leptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/1/135 |
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| author | Asli Ozmen Chinedu Nwabuobi Zhonghua Tang Xiaofang Guo Kellie Larsen Seth Guller Jacqueline Blas Monica Moore Umit A. Kayisli Charles J. Lockwood Ozlem Guzeloglu-Kayisli |
| author_facet | Asli Ozmen Chinedu Nwabuobi Zhonghua Tang Xiaofang Guo Kellie Larsen Seth Guller Jacqueline Blas Monica Moore Umit A. Kayisli Charles J. Lockwood Ozlem Guzeloglu-Kayisli |
| author_sort | Asli Ozmen |
| collection | DOAJ |
| description | Leptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the second trimester of human pregnancy and fall after labor. Several studies indicated a strong association between elevated placental leptin levels and preeclampsia (PE) pathogenesis and elevated serum interleukin-6 (IL-6) levels in PE patients. Therefore, we hypothesized that a local increase in placental leptin production induces IL-6 production in Hofbauer cells (HBCs) to contribute to PE-associated inflammation. We first investigated HBCs-specific IL-6 and leptin receptor (LEPR) expression and compared their immunoreactivity in PE vs. gestational age-matched control placentas. Subsequently, we examined the in vitro regulation of IL-6 as well as the phosphorylation levels of intracellular signaling proteins STAT3, STAT5, NF-κB, and ERK1/2 by increasing recombinant human leptin concentrations (10 to 1000 ng/mL) in primary cultured HBCs. Lastly, HBC cultures were incubated with leptin ± specific inhibitors of STAT3 or STAT5, or p65 NF-κB or ERK1/2 MAPK signaling cascades to determine relevant cascade(s) involved in leptin-mediated IL-6 regulation. Immunohistochemistry revealed ~three- and ~five-fold increases in IL-6 and LEPR expression, respectively, in HBCs from PE placentas. In vitro analysis indicated that leptin treatment in HBCs stimulate IL-6 in a concentration-dependent manner both at the transcriptional and secretory levels (<i>p</i> < 0.05). Moreover, leptin-treated HBC cultures displayed significantly increased phosphorylation levels of STAT5, p65 NF-κB, and ERK1/2 MAPK and pre-incubation of HBCs with a specific ERK1/2 MAPK inhibitor blocked leptin-induced IL-6 expression. Our in situ results show that HBCs contribute to the pathogenesis of PE by elevating IL-6 expression, and in vitro results indicate that induction of IL-6 expression in HBCs is primarily leptin-mediated. While HBCs display an anti-inflammatory phenotype in normal placentas, elevated levels of leptin may transform HBCs into a pro-inflammatory phenotype by activating ERK1/2 MAPK to augment IL-6 expression. |
| first_indexed | 2024-03-08T15:06:37Z |
| format | Article |
| id | doaj.art-b113f7b22ec640d09a29674aa2d5e85e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T15:06:37Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b113f7b22ec640d09a29674aa2d5e85e2024-01-10T14:58:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0125113510.3390/ijms25010135Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia PathogenesisAsli Ozmen0Chinedu Nwabuobi1Zhonghua Tang2Xiaofang Guo3Kellie Larsen4Seth Guller5Jacqueline Blas6Monica Moore7Umit A. Kayisli8Charles J. Lockwood9Ozlem Guzeloglu-Kayisli10Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USADepartment of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USALeptin plays a crucial role in regulating energy homoeostasis, neuroendocrine function, metabolism, and immune and inflammatory responses. The adipose tissue is a main source of leptin, but during pregnancy, leptin is also secreted primarily by the placenta. Circulating leptin levels peak during the second trimester of human pregnancy and fall after labor. Several studies indicated a strong association between elevated placental leptin levels and preeclampsia (PE) pathogenesis and elevated serum interleukin-6 (IL-6) levels in PE patients. Therefore, we hypothesized that a local increase in placental leptin production induces IL-6 production in Hofbauer cells (HBCs) to contribute to PE-associated inflammation. We first investigated HBCs-specific IL-6 and leptin receptor (LEPR) expression and compared their immunoreactivity in PE vs. gestational age-matched control placentas. Subsequently, we examined the in vitro regulation of IL-6 as well as the phosphorylation levels of intracellular signaling proteins STAT3, STAT5, NF-κB, and ERK1/2 by increasing recombinant human leptin concentrations (10 to 1000 ng/mL) in primary cultured HBCs. Lastly, HBC cultures were incubated with leptin ± specific inhibitors of STAT3 or STAT5, or p65 NF-κB or ERK1/2 MAPK signaling cascades to determine relevant cascade(s) involved in leptin-mediated IL-6 regulation. Immunohistochemistry revealed ~three- and ~five-fold increases in IL-6 and LEPR expression, respectively, in HBCs from PE placentas. In vitro analysis indicated that leptin treatment in HBCs stimulate IL-6 in a concentration-dependent manner both at the transcriptional and secretory levels (<i>p</i> < 0.05). Moreover, leptin-treated HBC cultures displayed significantly increased phosphorylation levels of STAT5, p65 NF-κB, and ERK1/2 MAPK and pre-incubation of HBCs with a specific ERK1/2 MAPK inhibitor blocked leptin-induced IL-6 expression. Our in situ results show that HBCs contribute to the pathogenesis of PE by elevating IL-6 expression, and in vitro results indicate that induction of IL-6 expression in HBCs is primarily leptin-mediated. While HBCs display an anti-inflammatory phenotype in normal placentas, elevated levels of leptin may transform HBCs into a pro-inflammatory phenotype by activating ERK1/2 MAPK to augment IL-6 expression.https://www.mdpi.com/1422-0067/25/1/135preeclampsiaplacentaHofbauer cellsleptinIL-6ERK1/2 |
| spellingShingle | Asli Ozmen Chinedu Nwabuobi Zhonghua Tang Xiaofang Guo Kellie Larsen Seth Guller Jacqueline Blas Monica Moore Umit A. Kayisli Charles J. Lockwood Ozlem Guzeloglu-Kayisli Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis International Journal of Molecular Sciences preeclampsia placenta Hofbauer cells leptin IL-6 ERK1/2 |
| title | Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis |
| title_full | Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis |
| title_fullStr | Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis |
| title_full_unstemmed | Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis |
| title_short | Leptin-Mediated Induction of IL-6 Expression in Hofbauer Cells Contributes to Preeclampsia Pathogenesis |
| title_sort | leptin mediated induction of il 6 expression in hofbauer cells contributes to preeclampsia pathogenesis |
| topic | preeclampsia placenta Hofbauer cells leptin IL-6 ERK1/2 |
| url | https://www.mdpi.com/1422-0067/25/1/135 |
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