We investigated whether Nuclear Factor-kappa B (NF-κB), 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 remodeling. We generated a doxycycline inducible transgenic mouse model to activate NF-κB specifically in the mammary epithelium through expression of a constitutively active form of IKK2, the upstream kinase in the classical NF-κB signaling cascade. We found that activation of NF-κB 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-κB during lactation with no additional involution signals had a similar effect. The observation that NF-κB is a key regulator of milk production led us to investigate the role of NF-κB 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-κB and milk loss during lactation. This milk loss was decreased by selective inhibition of NF-κB in mammary epithelium. Together, our data reveal that activation of NF-κB leads to milk clearance in the lactating mammary gland. Therefore, targeting of NF-κB signaling may prove therapeutic during mastitis in humans and could be beneficial for the dairy industry, where such infections have a major economic impact.

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