title: Tumor necrosis factor alpha induces LIF expression through ERK1/2 activation in mammary epithelial cells.
abstract: 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 (TNFalpha), 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 TNFalpha activity in the mammary epithelium might include regulation of LIF expression. This biological role would increase the significance of TNFalpha expression at the end of lactation. Our results show that TNFalpha 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 TNFalpha 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 TNFalpha treatment induced c-fos transcription, and blocking AP-1 activity resulted in a significant inhibition of TNFalpha-induced LIF expression. Finally, we found that TNFalpha was also able to trigger LIF expression and ERK1/2 activation in the mouse mammary gland in vivo. Therefore, our data suggest that TNFalpha may contribute to mammary gland involution by, among other activities, eliciting LIF expression through ERK1/2 and AP1 activation.
authors.affiliation: IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, UBA (1428), Buenos Aires, Argentina. caschere@fibertel.com.ar
authors.forename: Carolina Schere
authors.initials: CS
authors.lastname: Levy
authors.forename: Victoria
authors.initials: V
authors.lastname: Slomiansky
authors.forename: Albana
authors.initials: A
authors.lastname: Gattelli
authors.forename: Karen
authors.initials: K
authors.lastname: Nahmod
authors.forename: Federico
authors.initials: F
authors.lastname: Pelisch
authors.forename: Matias
authors.initials: M
authors.lastname: Blaustein
authors.forename: Anabella
authors.initials: A
authors.lastname: Srebrow
authors.forename: Omar A
authors.initials: OA
authors.lastname: Coso
authors.forename: Edith C
authors.initials: EC
authors.lastname: Kordon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3