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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	IL-4 IL-13 mammary glands cell proliferation STAT6 IRS protein Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/168b256a4ba941b89bd788f7ff90947f
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spelling	oai:doaj.org-article:168b256a4ba941b89bd788f7ff90947f2021-11-11T17:25:39ZIL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-110.3390/ijms2221120081422-00671661-6596https://doaj.org/article/168b256a4ba941b89bd788f7ff90947f2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/12008https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067T 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.Wan-Ju WuSue-Hong WangChun-Chi WuYi-An SuChin-Yin ChiangChing-Hong LaiTsung-Hsiang WangTsung-Lin ChengJia-Yu KuoTsai-Ching HsuTing-Hui LinYi-Ju LeeMDPI AGarticleIL-4IL-13mammary glandscell proliferationSTAT6IRS proteinBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12008, p 12008 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IL-4 IL-13 mammary glands cell proliferation STAT6 IRS protein Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	IL-4 IL-13 mammary glands cell proliferation STAT6 IRS protein Biology (General) QH301-705.5 Chemistry QD1-999 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
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.
format	article
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
title	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_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_sort	il-4 and il-13 promote proliferation of mammary epithelial cells through stat6 and irs-1
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/168b256a4ba941b89bd788f7ff90947f
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IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1

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