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Development 134 (15): 2739-2750

The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development

Walid T. Khaled1, Eliot K. C. Read1, Sandra E. Nicholson2, Fiona O. Baxter1, Amelia J. Brennan1, Paul J. Came1,*, Naomi Sprigg2, Andrew N. J. McKenzie3, and Christine J. Watson1,{dagger}

1 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
2 Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
3 Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, UK.

{dagger} Author for correspondence (e-mail: cjw53{at}cam.ac.uk)

Accepted for publication 30 May 2007.

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 (INF{gamma}; also known as Ifng) and Tnf{alpha} 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.

Key Words: Th2 cells • Cytokines • Mammary gland • Signalling • Mouse

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