Tumor necrosis factor alpha induces LIF expression through ERK1/2 activation in mammary epithelial cells

• Published in: Journal of cellular biochemistry Vol. 110; no. 4; pp. 857 - 865
• Main Authors: Levy, Carolina Schere, Slomiansky, Victoria, Gattelli, Albana, Nahmod, Karen, Pelisch, Federico, Blaustein, Matias, Srebrow, Anabella, Coso, Omar A., Kordon, Edith C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2010
• Subjects: Animals; AP-1; Blotting, Western; Cell Line; Electrophoretic Mobility Shift Assay; Enzyme Activation; Humans; Immunohistochemistry; involution; Leukemia Inhibitory Factor - metabolism; LIF; mammary epithelial cells; mammary gland; Mammary Glands, Human - cytology; Mammary Glands, Human - enzymology; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; TNFα; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.22595

It has been reported that expression of tumor necrosis factor superfamily members occur at the onset of the mammary gland post‐lactational involution. One of these proteins, tumor necrosis factor alpha (TNFα), is a major mediator of inflammation that is able to induce expression of several cytokines. Leukemia inhibitory factor (LIF) is an inflammatory cytokine that is induced and plays a fundamental role during post‐lactational involution of the mammary gland. Therefore, our goal was to determine whether TNFα activity in the mammary epithelium might include regulation of LIF expression. This biological role would increase the significance of TNFα expression at the end of lactation. Our results show that TNFα was able to induce LIF transcription through ERK1/2 activation in a non‐tumorigenic mouse mammary epithelial cell line, SCp2. We found that activation of TNFα receptor‐2 (TNFR2) was specifically involved in triggering this signaling pathway. In addition, our data suggest the participation of AP‐1 transcription factor family members in this pathway. We determined that TNFα treatment induced c‐fos transcription, and blocking AP‐1 activity resulted in a significant inhibition of TNFα‐induced LIF expression. Finally, we found that TNFα was also able to trigger LIF expression and ERK1/2 activation in the mouse mammary gland in vivo. Therefore, our data suggest that TNFα may contribute to mammary gland involution by, among other activities, eliciting LIF expression through ERK1/2 and AP1 activation. J. Cell. Biochem. 110: 857–865, 2010. © 2010 Wiley‐Liss, Inc.