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

SCHERE LEVY C.; SLOMIANSKY V; GATTELLI, A.; NAHMOD K.; PELISCH F.; BLAUSTEIN M.; SREBROW A.; COSO O.; KORDON E.

JOURNAL OF CELLULAR BIOCHEMISTRY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2010 vol. 110 p. 857 - 865

0730-2312

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 (TNFa), 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 TNFa activity in the mammary epithelium might include regulation of LIF expression. This biological role would increase the significance of TNFa expression at the end of lactation. Our results show that TNFa 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 TNFa 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 TNFa treatment induced c-fos transcription, and blocking AP-1 activity resulted in a significant inhibition of TNFa-induced LIF expression. Finally, we found that TNFa was also able to trigger LIF expression and ERK1/2 activation in the mouse mammary gland in vivo. Therefore, our data suggest that TNFa may contribute to mammary gland involution by, among other activities, eliciting LIF expression through ERK1/2 and AP1 activation.