IL-4 and IL-13 Promote Proliferation of Mammary Epithelial Cells through STAT6 and IRS-1

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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Main Authors: 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
Format: article
Language:EN
Published: MDPI AG 2021
Subjects:
IL-4
IL-13
mammary glands
cell proliferation
STAT6
IRS protein
Biology (General)
QH301-705.5
Chemistry
QD1-999
Online Access:https://doaj.org/article/168b256a4ba941b89bd788f7ff90947f
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Summary: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.

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