Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor
Background: Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the interleukin-1β (IL-1β) family, interleukin-33 (IL-33) has been shown to be involved in normal pregnancy as well as a variety of pregnancy-related disorder. This study aims to investi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75072 |
| _version_ | 1818027526883115008 |
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| author | Li Chen Zhenzhen Song Xiaowan Cao Mingsong Fan Yan Zhou Guoying Zhang |
| author_facet | Li Chen Zhenzhen Song Xiaowan Cao Mingsong Fan Yan Zhou Guoying Zhang |
| author_sort | Li Chen |
| collection | DOAJ |
| description | Background: Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the interleukin-1β (IL-1β) family, interleukin-33 (IL-33) has been shown to be involved in normal pregnancy as well as a variety of pregnancy-related disorder. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor.
Methods: Myometrium samples from term pregnant (≥37 weeks gestation) women were either frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to assess the distribution of IL-33. Cultured cells were incubated with lipopolysaccharide (LPS) to mimic inflammation as well as in the presence of 4μ8C (IRE1 inhibitor III) to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator.
Results: LPS reduced the expression of nuclear IL-33 in a time-limited manner and induced ER stress. However, knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of nuclear factor kappa-B (NF-κB), and P38 mitogen-activated protein kinase (P38 MAPK). In addition, siRNA IL-33 further stimulates LPS enhanced cyclooxygenase-2 (COX-2) expression via NF-κB and p38 pathways. IL-33 expression was decreased in the nucleus with the onset of labor. LPS-induced ER stress and increased expression of the labor-associated gene, COX-2, as well as IL-6 and IL-8 in cultured myometrial cells. IL-33 also increased COX-2 expression, but after it was knocked down, the stimulating effect of LPS on calcium was enhanced. 4μ8C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased which was accompanied by phosphorylated NF-κB and p38.
Conclusions: These data suggest that IL-33 may be involved in the initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells.
Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81300507). |
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| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:49:18Z |
| publishDate | 2022-08-01 |
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| series | eLife |
| spelling | doaj.art-cd9f2a474aef4d9b845a3adbe7223c122022-12-22T02:01:40ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.75072Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of laborLi Chen0https://orcid.org/0000-0002-6673-2963Zhenzhen Song1Xiaowan Cao2Mingsong Fan3Yan Zhou4Guoying Zhang5Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Obstetrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, ChinaDepartment of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaBackground: Inflammation is currently recognized as one of the major causes of premature delivery. As a member of the interleukin-1β (IL-1β) family, interleukin-33 (IL-33) has been shown to be involved in normal pregnancy as well as a variety of pregnancy-related disorder. This study aims to investigate the potential function of IL-33 in uterine smooth muscle cells during labor. Methods: Myometrium samples from term pregnant (≥37 weeks gestation) women were either frozen or cells were isolated and cultured. Immunohistochemistry and western blotting were used to assess the distribution of IL-33. Cultured cells were incubated with lipopolysaccharide (LPS) to mimic inflammation as well as in the presence of 4μ8C (IRE1 inhibitor III) to block endoplasmic reticulum (ER) stress and BAPTA-AM, a calcium chelator. Results: LPS reduced the expression of nuclear IL-33 in a time-limited manner and induced ER stress. However, knockdown of IL-33 increased LPS-induced calcium concentration, ER stress and phosphorylation of nuclear factor kappa-B (NF-κB), and P38 mitogen-activated protein kinase (P38 MAPK). In addition, siRNA IL-33 further stimulates LPS enhanced cyclooxygenase-2 (COX-2) expression via NF-κB and p38 pathways. IL-33 expression was decreased in the nucleus with the onset of labor. LPS-induced ER stress and increased expression of the labor-associated gene, COX-2, as well as IL-6 and IL-8 in cultured myometrial cells. IL-33 also increased COX-2 expression, but after it was knocked down, the stimulating effect of LPS on calcium was enhanced. 4μ8C also inhibited the expression of COX-2 markedly. The expression of calcium channels on the membrane and intracellular free calcium ion were both increased which was accompanied by phosphorylated NF-κB and p38. Conclusions: These data suggest that IL-33 may be involved in the initiation of labor by leading to stress of the ER via an influx of calcium ions in human uterine smooth muscle cells. Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81300507).https://elifesciences.org/articles/75072preterm labormyometriuminterleukin-33inflammationcalcium channelsstress |
| spellingShingle | Li Chen Zhenzhen Song Xiaowan Cao Mingsong Fan Yan Zhou Guoying Zhang Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor eLife preterm labor myometrium interleukin-33 inflammation calcium channels stress |
| title | Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor |
| title_full | Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor |
| title_fullStr | Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor |
| title_full_unstemmed | Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor |
| title_short | Interleukin-33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor |
| title_sort | interleukin 33 regulates the endoplasmic reticulum stress of human myometrium via an influx of calcium during initiation of labor |
| topic | preterm labor myometrium interleukin-33 inflammation calcium channels stress |
| url | https://elifesciences.org/articles/75072 |
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