Activation of nuclear factor kappa B in mammary epithelium promotes milk loss during mammary development and infection.
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.
Connelly
Linda
L
Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.
Barham
Whitney
W
Pigg
Rachel
R
Saint-Jean
Leshana
L
Sherrill
Taylor
T
Cheng
Dong-Sheng
DS
Chodosh
Lewis A
LA
Blackwell
Timothy S
TS
Yull
Fiona E
FE
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
D008070:Lipopolysaccharides; D008894:Milk Proteins; D016328:NF-kappa B; D004318:Doxycycline