IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1
T helper (Th)2 cytokines such as interleukin (IL)-4 and IL-13 control immune function by acting on leukocytes. They also regulate multiple responses in non-hematopoietic cells. During pregnancy, IL-4 and IL-13 facilitate alveologenesis of mammary glands. This particular morphogenesis generates alveo...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/21/12008 |
| _version_ | 1797512336232153088 |
|---|---|
| author | Wan-Ju Wu Sue-Hong Wang Chun-Chi Wu Yi-An Su Chin-Yin Chiang Ching-Hong Lai Tsung-Hsiang Wang Tsung-Lin Cheng Jia-Yu Kuo Tsai-Ching Hsu Ting-Hui Lin Yi-Ju Lee |
| author_facet | Wan-Ju Wu Sue-Hong Wang Chun-Chi Wu Yi-An Su Chin-Yin Chiang Ching-Hong Lai Tsung-Hsiang Wang Tsung-Lin Cheng Jia-Yu Kuo Tsai-Ching Hsu Ting-Hui Lin Yi-Ju Lee |
| author_sort | Wan-Ju Wu |
| collection | DOAJ |
| description | T helper (Th)2 cytokines such as interleukin (IL)-4 and IL-13 control immune function by acting on leukocytes. They also regulate multiple responses in non-hematopoietic cells. During pregnancy, IL-4 and IL-13 facilitate alveologenesis of mammary glands. This particular morphogenesis generates alveoli from existing ducts and requires substantial cell proliferation. Using 3D cultures of primary mouse mammary epithelial cells, we demonstrate that IL-4 and IL-13 promote cell proliferation, leading to enlargement of mammary acini with partially filled lumens. The mitogenic effects of IL-4 and IL-13 are mediated by STAT6 as inhibition of STAT6 suppresses cell proliferation and improves lumen formation. In addition, IL-4 and IL-13 stimulate tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Prolonged treatment with these cytokines leads to increased IRS-1 abundance, which, in turn, amplifies IL-4- and IL-13-stimulated IRS-1 tyrosine phosphorylation. Through signaling crosstalk between IL-4/IL-13 and insulin, a hormone routinely included in mammary cultures, IRS-1 tyrosine phosphorylation is further enhanced. Lowering IRS-1 expression reduces cell proliferation, suggesting that IRS-1 is involved in IL-4- and IL-13-stimulated cell proliferation. Thus, a Th2-dominant cytokine milieu during pregnancy confers mammary gland development by promoting cell proliferation. |
| first_indexed | 2024-03-10T06:00:22Z |
| format | Article |
| id | doaj.art-168b256a4ba941b89bd788f7ff90947f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:00:22Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-168b256a4ba941b89bd788f7ff90947f2023-11-22T21:01:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122211200810.3390/ijms222112008IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1Wan-Ju Wu0Sue-Hong Wang1Chun-Chi Wu2Yi-An Su3Chin-Yin Chiang4Ching-Hong Lai5Tsung-Hsiang Wang6Tsung-Lin Cheng7Jia-Yu Kuo8Tsai-Ching Hsu9Ting-Hui Lin10Yi-Ju Lee11Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 500, TaiwanDepartment of Biomedical Sciences, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanDepartment of Biomedical Sciences, Chung Shan Medical University, Taichung 402, TaiwanInstitute of Medicine, Chung Shan Medical University, Taichung 402, TaiwanT helper (Th)2 cytokines such as interleukin (IL)-4 and IL-13 control immune function by acting on leukocytes. They also regulate multiple responses in non-hematopoietic cells. During pregnancy, IL-4 and IL-13 facilitate alveologenesis of mammary glands. This particular morphogenesis generates alveoli from existing ducts and requires substantial cell proliferation. Using 3D cultures of primary mouse mammary epithelial cells, we demonstrate that IL-4 and IL-13 promote cell proliferation, leading to enlargement of mammary acini with partially filled lumens. The mitogenic effects of IL-4 and IL-13 are mediated by STAT6 as inhibition of STAT6 suppresses cell proliferation and improves lumen formation. In addition, IL-4 and IL-13 stimulate tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Prolonged treatment with these cytokines leads to increased IRS-1 abundance, which, in turn, amplifies IL-4- and IL-13-stimulated IRS-1 tyrosine phosphorylation. Through signaling crosstalk between IL-4/IL-13 and insulin, a hormone routinely included in mammary cultures, IRS-1 tyrosine phosphorylation is further enhanced. Lowering IRS-1 expression reduces cell proliferation, suggesting that IRS-1 is involved in IL-4- and IL-13-stimulated cell proliferation. Thus, a Th2-dominant cytokine milieu during pregnancy confers mammary gland development by promoting cell proliferation.https://www.mdpi.com/1422-0067/22/21/12008IL-4IL-13mammary glandscell proliferationSTAT6IRS protein |
| spellingShingle | Wan-Ju Wu Sue-Hong Wang Chun-Chi Wu Yi-An Su Chin-Yin Chiang Ching-Hong Lai Tsung-Hsiang Wang Tsung-Lin Cheng Jia-Yu Kuo Tsai-Ching Hsu Ting-Hui Lin Yi-Ju Lee IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1 International Journal of Molecular Sciences IL-4 IL-13 mammary glands cell proliferation STAT6 IRS protein |
| title | IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1 |
| title_full | IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1 |
| title_fullStr | IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1 |
| title_full_unstemmed | IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1 |
| title_short | IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1 |
| title_sort | il 4 and il 13 promote proliferation of mammary epithelial cells through stat6 and irs 1 |
| topic | IL-4 IL-13 mammary glands cell proliferation STAT6 IRS protein |
| url | https://www.mdpi.com/1422-0067/22/21/12008 |
| work_keys_str_mv | AT wanjuwu il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT suehongwang il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT chunchiwu il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT yiansu il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT chinyinchiang il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT chinghonglai il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT tsunghsiangwang il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT tsunglincheng il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT jiayukuo il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT tsaichinghsu il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT tinghuilin il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 AT yijulee il4andil13promoteproliferationofmammaryepithelialcellsthroughstat6andirs1 |