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This Article Full Text (PDF) All Versions of this Article: jas.2008-1333v1 87/13_suppl/35    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Watson, C. J Search for Related Content PubMed PubMed Citation Articles by Watson, C. J

Immune cell regulators in mouse mammary development and involution

Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom

cjw53{at}cam.ac.uk

Abstract

Dramatic changes in cell composition and function occur in the mammary gland during a pregnancy-lactation-involution cycle. We have investigated the transcriptional changes associated with these biological events using microarray analysis and identified the critical genes involved using genetically modified mice. Two surprising findings arose from these studies. First, the microarray data showed that post-lactational regression was associated with an acute phase inflammatory response, in addition to cell death. Conditional deletion of signal transducer and activator of transcription (Stat)3 or the nuclear factor (NF)-B regulatory kinase inhibitor of B kinase (IKK)β, resulted in a failure of cell death induction during involution, an indication that these signaling pathways are essential mediators of the involution process. Both Stat3 and NF-B have been shown to regulate acute phase gene expression in addition to apoptosis regulators. Four distinct transcriptional profiles are present in the first 4 d of involution whereas there are three in lactation. At the peak of lactation (i.e., d 10 in mouse) over 400 genes reach their maximum expression level before declining dramatically in the first 12 h of involution. A reciprocal pattern was observed for over 500 genes that were specifically upregulated within the first 12 h of forced involution. We are now investigating the role of a subset of these genes in involution. We also uncovered a role for genes normally associated with immune cell signaling in differentiation of luminal mammary epithelial cells during pregnancy. Genetic deletion of the transcription factor Stat6 resulted in delayed development during pregnancy and this phenotype was recapitulated in mammary tissue from interleukin (IL)-4 and IL-13 doubly deficient mice. Furthermore, we showed that mammary epithelial cells secrete T cell regulatory cytokines. T helper type 1 cytokines, such as interferon- and IL-12a, are secreted by undifferentiated mammary epithelial cells whereas T_H type 2 cytokines including IL-4 and IL-13 are secreted by differentiated cells. This unexpected finding demonstrates a role for immune cell signaling in mammary epithelial cell fate and function.

Key Words: apoptosis • involution • immune • mammary gland • microarray • signal transducer and activator of transcription