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

Abstract

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.

Mast cell ontogeny: From fetal development to life‐long health and disease

“…In the pubertal and post‐lactational mammary gland, mast cells also produce the protease plasma kallikrein, which activates the plasminogen cascade 127 . Mast cell proteases may also enhance IL‐33 signaling 133 and promote stromal remodeling via secretion of pro‐inflammatory cytokines like IL‐6 134,135 and IL‐13 136,137 . It is thus possible that effectors released by mast cells directly affect mammary gland remodeling, independently of other immune cells 128 …”

“…127 Mast cell proteases may also enhance IL-33 signaling 133 and promote stromal remodeling via secretion of pro-inflammatory cytokines like IL-6 134,135 and IL-13. 136,137 It is thus possible that effectors released by mast cells directly affect mammary gland remodeling, independently of other immune cells. 128 Finally, single cell transcriptional profiling recently demonstrated that the earliest mast cells found in human fetuses express transcripts for pro-inflammatory cytokines and chemokines involved in recruitment of endothelial cells.…”

The Role of Insulin Receptor Substrate Proteins in Bronchopulmonary Dysplasia and Asthma: New Potential Perspectives

“…These complexes trigger the activation of JAK that phosphorylate the specific tyrosine motifs [ 63 ]. During these auto- and cross-phosphorylations, JAK1, JAK2, and JAK3 consequently interact with IL4R-α, IL13R-α1, and -γ-chain, respectively, which are crucial to present docking sites for IRS proteins [ 64 ]. The IRS proteins specifically bind to the tyrosine phosphorylated NPXY motif of the cytoplasmic tail of the receptors, which is also defined as the insulin and IL-4 receptor (I4R) motif [ 65 ].…”

Recent Advances in the Inhibition of the IL-4 Cytokine Pathway for the Treatment of Allergen-Induced Asthma

“…Whilst STAT6 activates allergy symptoms, IRSs are involved with cellular proliferation. Both the IL-4 and IL-13 pathways play roles in the inflammation associated with allergies; however, they also play fundamental roles in cellular function [18][19][20] (Figure 1).…”

“…Whilst STAT6 activates allergy symptoms, IRSs are involved with cellular proliferation. Both the IL-4 and IL-13 pathways play roles in the inflammation associated with allergies; however, they also play fundamental roles in cellular function [18][19][20] (Figure 1). STAT6 is activated by both the IL-4 and IL-13 pathways, though this is largely dependent on the cell type, as are the effects of the STAT6 molecule.…”