Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation
The fetal inflammatory response, a key contributor of infection-associated preterm birth (PTB), is mediated by nuclear factor kappa B (NF-kB) activation. Na<sup>+</sup>/H<sup>+</sup> exchanger regulatory factor-1 (NHERF1) is an adapter protein that can regulate intracellular...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/20/7747 |
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| author | Ananth Kumar Kammala Samantha Sheller-Miller Enkhtuya Radnaa Talar Kechichian Hariharan Subramanian Ramkumar Menon |
| author_facet | Ananth Kumar Kammala Samantha Sheller-Miller Enkhtuya Radnaa Talar Kechichian Hariharan Subramanian Ramkumar Menon |
| author_sort | Ananth Kumar Kammala |
| collection | DOAJ |
| description | The fetal inflammatory response, a key contributor of infection-associated preterm birth (PTB), is mediated by nuclear factor kappa B (NF-kB) activation. Na<sup>+</sup>/H<sup>+</sup> exchanger regulatory factor-1 (NHERF1) is an adapter protein that can regulate intracellular signal transduction and thus influence NF-kB activation. Accordingly, NHERF1 has been reported to enhance proinflammatory cytokine release and amplify inflammation in a NF-kB-dependent fashion in different cell types. The objective of this study was to examine the role of NHERF1 in regulating fetal membrane inflammation during PTB. We evaluated the levels of NHERF1 in human fetal membranes from term labor (TL), term not in labor (TNIL), and PTB and in a CD1 mouse model of PTB induced by lipopolysaccharide (LPS). Additionally, primary cultures of fetal membrane cells were treated with LPS, and NHERF1 expression and cytokine production were evaluated. Gene silencing methods using small interfering RNA targeting NHERF1 were used to determine the functional relevance of NHERF1 in primary cultures. NHERF1 expression was significantly (<i>p</i> < 0.001) higher in TL and PTB membranes compared to TNIL membranes, and this coincided with enhanced (<i>p</i> < 0.01) interleukin (IL)-6 and IL-8 expression levels. LPS-treated animals delivering PTB had increased levels of NHERF1, IL-6, and IL-8 compared to phosphate-buffered saline (PBS; control) animals. Silencing of NHERF1 expression resulted in a significant reduction in NF-kB activation and IL-6 and IL-8 production as well as increased IL-10 production. In conclusion, downregulation of NHERF1 increased anti-inflammatory IL-10, and reducing NHERF1 expression could be a potential therapeutic strategy to reduce the risk of infection/inflammation associated with PTB. |
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| language | English |
| last_indexed | 2024-03-10T15:29:38Z |
| publishDate | 2020-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-7cc183835177417f971d0e0a4abd88352023-11-20T17:45:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120774710.3390/ijms21207747Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane InflammationAnanth Kumar Kammala0Samantha Sheller-Miller1Enkhtuya Radnaa2Talar Kechichian3Hariharan Subramanian4Ramkumar Menon5Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USADepartment of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USADepartment of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USADepartment of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USADepartment of Physiology, Michigan State University, 567 Wilson Rd, East Lansing, MI 48824, USADepartment of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and Perinatal Research, The University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1062, USAThe fetal inflammatory response, a key contributor of infection-associated preterm birth (PTB), is mediated by nuclear factor kappa B (NF-kB) activation. Na<sup>+</sup>/H<sup>+</sup> exchanger regulatory factor-1 (NHERF1) is an adapter protein that can regulate intracellular signal transduction and thus influence NF-kB activation. Accordingly, NHERF1 has been reported to enhance proinflammatory cytokine release and amplify inflammation in a NF-kB-dependent fashion in different cell types. The objective of this study was to examine the role of NHERF1 in regulating fetal membrane inflammation during PTB. We evaluated the levels of NHERF1 in human fetal membranes from term labor (TL), term not in labor (TNIL), and PTB and in a CD1 mouse model of PTB induced by lipopolysaccharide (LPS). Additionally, primary cultures of fetal membrane cells were treated with LPS, and NHERF1 expression and cytokine production were evaluated. Gene silencing methods using small interfering RNA targeting NHERF1 were used to determine the functional relevance of NHERF1 in primary cultures. NHERF1 expression was significantly (<i>p</i> < 0.001) higher in TL and PTB membranes compared to TNIL membranes, and this coincided with enhanced (<i>p</i> < 0.01) interleukin (IL)-6 and IL-8 expression levels. LPS-treated animals delivering PTB had increased levels of NHERF1, IL-6, and IL-8 compared to phosphate-buffered saline (PBS; control) animals. Silencing of NHERF1 expression resulted in a significant reduction in NF-kB activation and IL-6 and IL-8 production as well as increased IL-10 production. In conclusion, downregulation of NHERF1 increased anti-inflammatory IL-10, and reducing NHERF1 expression could be a potential therapeutic strategy to reduce the risk of infection/inflammation associated with PTB.https://www.mdpi.com/1422-0067/21/20/7747NHERF1amniochorioninfectionpreterm birthNF-kBinterleukin-10 |
| spellingShingle | Ananth Kumar Kammala Samantha Sheller-Miller Enkhtuya Radnaa Talar Kechichian Hariharan Subramanian Ramkumar Menon Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation International Journal of Molecular Sciences NHERF1 amniochorion infection preterm birth NF-kB interleukin-10 |
| title | Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation |
| title_full | Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation |
| title_fullStr | Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation |
| title_full_unstemmed | Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation |
| title_short | Sodium Hydrogen Exchanger Regulatory Factor-1 (NHERF1) Regulates Fetal Membrane Inflammation |
| title_sort | sodium hydrogen exchanger regulatory factor 1 nherf1 regulates fetal membrane inflammation |
| topic | NHERF1 amniochorion infection preterm birth NF-kB interleukin-10 |
| url | https://www.mdpi.com/1422-0067/21/20/7747 |
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