title: 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.
abstract: 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.
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, and Hematology Branch/NIH, Building 8 Room 101, 8 Center Drive, Bethesda, MD 20892, USA. LingZ@intra.niddk.nih.gov
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Melenhorst
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
mesh_terms: D000818:Animals; D017209:Apoptosis; D051152:Clusterin; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D018832:Molecular Chaperones / Q000235:genetics; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000032:analysis; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000032:analysis / Q000502:physiology*; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; C495243:Clu protein, mouse; D051152:Clusterin; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D015850:Interleukin-6; D008894:Milk Proteins; D018832:Molecular Chaperones; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases