title: The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development.
abstract: Naïve T helper cells differentiate into Th1 and Th2 subsets, which have unique cytokine signatures, activators and transcriptional targets. The Th1/Th2 cytokine milieu is a key paradigm in lineage commitment, and IL-4 (Il4), IL-13 (Il13) and Stat6 are important mediators of Th2 development. We show here, for the first time, that this paradigm applies also to mammary epithelial cells, which undergo a switch from Th1 to Th2 cytokine production upon the induction of differentiation. Thus, the Th1 cytokines IL-12 (Il12), interferon gamma (INFgamma; also known as Ifng) and Tnfalpha are downregulated concomitantly with the upregulation of the Th2 cytokines IL-4, IL-13 and IL-5 (Il5) as epithelial cells commit to the luminal lineage. Moreover, we show that Th2 cytokines play a crucial role in mammary gland development in vivo, because differentiation and alveolar morphogenesis are reduced in both Stat6 and IL-4/IL-13 doubly deficient mice during pregnancy. This unexpected discovery demonstrates a role for immune cell cytokines in epithelial cell fate and function, and adds an unexpected tier of complexity to the previously held paradigm that steroid and peptide hormones are the primary regulators of mammary gland development.
authors.affiliation: Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Walid T
authors.initials: WT
authors.lastname: Khaled
authors.forename: Eliot K C
authors.initials: EK
authors.lastname: Read
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.forename: Fiona O
authors.initials: FO
authors.lastname: Baxter
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Brennan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Came
authors.forename: Naomi
authors.initials: N
authors.lastname: Sprigg
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Watson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008954:Models, Biological; D011247:Pregnancy; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018793:Interleukin-13; D050800:STAT6 Transcription Factor; D015847:Interleukin-4