TNF ALPHA DOWN-REGULATION BY TRISTETRAPROLIN (TTP) IS RELEVANT FOR MOUSE LACTATION MAINTENANCE

MARÍA VICTORIA GODDIO; ALBANA GATTELLI; PEREZ CUERVO L; JOHANNA TOCCI; NANCY E. HYNES; MEISS ROBERTO; EDITH C KORDON

Congreso; LXI Reunión Anual SAIC; 2016

From pregnancy to lactation, lobulo-alveolar growthis followed by the complete differentiation of mammaryepithelium, which allows the production and secretion ofmilk proteins. At weaning, a rapid switch from survivalto death signaling occurs, leading to involution, whichinvolves extensive remodeling and an innate immuneresponse. TTP is a RNA-binding protein that leads todegradation of messenger RNA of pro-inflammatorycytokine and invasiveness-associated genes. We havepreviously shown that in the mouse mammary gland, TTPexpression is induced during lactation and repressed afterweaning. We have also determined, using conditional KOmice (TTP-MGKO), in which TTP expression is specificallydown-regulated in the mammary secretory cells, that TTPprevents early cell death during lactation. Then, we found(by cytochemistry, immunohistochemistry, western blotand RT-qPCR analysis of mammary tissue) that TTPMGKOglands show signs of involution at mid-lactation,like the presence of apoptotic epithelial cells, increasedlevels of cleft caspase-3, inflammatory cytokines (TNFα,LIF and IL-6) and STAT3 phosphorylation, as well as adecrease in AKT phosphorylation. As TNFα mRNA is amain target for TTP destabilization activity, we speculatedthat the increase of this specific cytokine would play aprimordial role in the development of the phenotype in thetransgenic animals. To test this hypothesis, TTP-MGKOmice were inoculated with TNFα blocking antibody ?Etanercept?during the first 15 days of lactation (n=4 in eachgroup). This caused a significant reduction in mammarycell death, without modifying the high cytokine expressionand Stat3 phosphorylation levels observed in the lactatingTTP-MGKO placebo treated or untreated mice. Theseobservations confirm that TTP significantly contributesto lactation maintenance, and shows that keeping TNFαlevels low is fundamental for mammary cell survival duringthat period.