title: Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary development and infection.
abstract: We investigated whether nuclear factor kappa B (NF-kappaB), which exhibits a regulated pattern of activity during murine mammary gland development, plays an important role during lactation and involution, when milk production ceases and the gland undergoes apoptosis and re-modeling. We generated a doxycycline inducible transgenic mouse model to activate NF-kappaB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappaB signaling cascade. We found that activation of NF-kappaB during involution resulted in a more rapid reduction in milk levels and increased cleavage of caspase-3, an indicator of apoptosis. We also found that activation of NF-kappaB during lactation with no additional involution signals had a similar effect. The observation that NF-kappaB is a key regulator of milk production led us to investigate the role of NF-kappaB during mastitis, an infection of the mammary gland in which milk loss is observed. Mammary gland injection of E. coli LPS resulted in activation of NF-kappaB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappaB in mammary epithelium. Together, our data reveal that activation of NF-kappaB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappaB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Connelly
authors.forename: Whitney
authors.initials: W
authors.lastname: Barham
authors.forename: Rachel
authors.initials: R
authors.lastname: Pigg
authors.forename: Leshana
authors.initials: L
authors.lastname: Saint-Jean
authors.forename: Taylor
authors.initials: T
authors.lastname: Sherrill
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D007774:Lactation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000473:pathology*; D008413:Mastitis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008892:Milk / Q000187:drug effects / Q000378:metabolism*; D008894:Milk Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D008894:Milk Proteins; D016328:NF-kappa B; D004318:Doxycycline