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Loss of Interleukin 6 Results in Delayed Mammary Gland Involution: A Possible Role for Mitogen-Activated Protein Kinase and Not Signal Transducer and Activator of Transcription 3

Laboratory of Genetics and Physiology (L.Z., L.H.), National Institute of Diabetes and Digestive and Kidney Diseases, and Hematology Branch (J.J.M.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Lothar Hennighausen, Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Building 8, Room 101, Bethesda, MD 20892-0822. E-mail: hennighausen{at}nih.gov or LingZ{at}intra.niddk.nih.gov.

We have investigated the role of IL-6 in the initiation and progression of mouse mammary gland involution in IL-6-null mice. This study was based on the hypothesis that IL-6 is the activating cytokine for signal transducer and activator of transcription 3 (Stat), the transcription factor whose presence is required for controlled mammary gland involution. We now show that expression of IL-6 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 IL-6 into virgin and lactating mice activates Stat3 in mammary epithelium. The in vivo role of IL-6 was investigated using mutant mice. Involution of mammary tissue in IL-6-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 IL-6 status. This suggests that either IL-6 does not induce Stat3 in vivo or its absence is compensated for by other cytokines, such as leukemia-inhibitory factor (LIF). In contrast, the increase of p44/42 MAPK (ERK1/2) phosphorylation at the onset of involution was dependent on the presence of IL-6. Delayed involution corresponded with a decrease of epithelial cell death, and a delayed induction of Bax and sulfated glycoprotein 2 (SGP2, or clusterin) expression. Our experiments demonstrate on a genetic level that IL-6 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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