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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,*,
Andrew N. J. McKenzie3, and
Christine J. Watson1,
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,
Author for correspondence (e-mail:
Accepted for publication 30 May 2007.
Naïve T helper cells differentiate into Th1 and Th2 subsets,which
have unique cytokine signatures, activators and transcriptionaltargets. The
Th1/Th2 cytokine milieu is a key paradigm in lineagecommitment, and IL-4
(Il4), IL-13 (Il13) and Stat6 are importantmediators 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
uponthe induction of differentiation. Thus, the Th1 cytokines IL-12(Il12),
interferon gamma (INF; also known as Ifng) and Tnf are
downregulatedconcomitantly with the upregulation of the Th2 cytokines IL-4,
IL-13and IL-5 (Il5) as epithelial cells commit to the luminal lineage.
Moreover,we show that Th2 cytokines play a crucial role in mammary gland
developmentin vivo, because differentiation and alveolar morphogenesisare
reduced in both Stat6 and IL-4/IL-13 doubly deficient miceduring pregnancy.
This unexpected discovery demonstrates a rolefor immune cell cytokines in
epithelial cell fate and function,and adds an unexpected tier of complexity
to the previouslyheld paradigm that steroid and peptide hormones are the
primaryregulators of mammary gland development.