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-kappa B), 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-kappa B specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-kappa B signaling cascade. We found that activation of NF-kappa B 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-kappa B during lactation with no additional involution signals had a similar effect. The observation that NF-kappa B is a key regulator of milk production led us to investigate the role of NF-kappa B 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-kappa B and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-kappa B in mammary epithelium. Together, our data reveal that activation of NF-kappa B leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-kappa B signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact. J. Cell. Physiol. 222: 73-81, 2010. (C) 2009 Wiley-Liss, Inc.