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Submitted on December 7, 2001
Accepted on August 15, 2002
1 Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases; Hematology Branch, National Heart Lung and Blood Institute; NIH, Bethesda, MD 20892
* To whom correspondence should be addressed. E-mail: hennighausen{at}nih.gov.
We have investigated the role of IL6 in the initiation and progression of mouse mammary gland involution in IL6-null mice. This study was based on the hypothesis that IL6 is the activating cytokine for Stat3, the transcription factor whose presence is required for controlled mammary gland involution. We now show that expression of IL6 is low during lactation but increases at the onset of involution in parallel with the activation of Stat3 and p44/42 MAPK. Moreover, we demonstrated that injection of IL6 into virgin and lactating mice activates Stat3 in mammary epithelium. The in vivo role of IL6 was investigated using mutant mice. Involution of mammary tissue in IL6-null mice was delayed similar to that seen in mammary conditional Stat3- and Bax-null mice. However, Stat3 activation during involution was independent of the IL6 status. This suggests that either IL6 does not induce Stat3 in vivo or its absence is compensated for by other cytokines, such as LIF. In contrast, the increase of p44/42 MAPK (Erk1/2) phosphorylation at the onset of involution was dependent on the presence of IL6. Delayed involution corresponded with a decrease of epithelial cell death, and a delayed induction of Bax and SGP2 expression. Our experiments demonstrate on a genetic level that IL6 contributes to the induction of the controlled remodeling of mammary tissue during involution, possibly through the MAPK pathway and by mediating the expression of the cell death protein Bax.
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