Prolactin and glucocorticoid signaling induces lactation-specific tight junctions concurrent with β-casein expression in mammary epithelial cells

Abstract

Alveolar mammary epithelial cells (MECs) in mammary glands are highly specialized cells that produce milk for suckling infants. Alveolar MECs also form less permeable tight junctions (TJs) to prevent the leakage of milk components after parturition. In the formation process of less permeable TJs, MECs show a selective downregulation of Cldn4 and a localization change of Cldn3. To investigate what induces less permeable TJs through these compositional changes in Cldns, we focused on two lactogenesis-related hormones: prolactin (Prl) and glucocorticoids. Prl caused a downregulation of Cldn3 and Cldn4 with the formation of leaky TJs in MECs in vitro. Prl-treated MECs also showed low β-casein expression with the activation of STAT5 signaling. By contrast, dexamethasone (Dex), a glucocorticoid analogue, upregulated Cldn3 and Cldn4, concurrent with the formation of less permeable TJs and the activation of glucocorticoid signaling without the expression of β-casein. Cotreatment with Prl and Dex induced the selective downregulation of Cldn4 and the concentration of Cldn3 in the region of TJs concurrent with less permeable TJ formation and high β-casein expression. The inhibition of Prl secretion by bromocriptine in lactating mice induced the upregulation of Cldn3 and Cldn4 concurrent with the downregulation of milk production. These results indicate that the coactivation of Prl and glucocorticoid signaling induces lactation-specific less permeable TJs concurrent with lactogenesis.

Developmental Expression of Claudins in the Mammary Gland

“…Primary cells (MEC) were isolated from the mammary glands of virgin ICR mice and maintained in culture [64], In the MEC without hormones epithelial permeability was low and little claudin-3 and claudin-4 was localized to the tight junction. Addition of glucocorticoid alone promoted the barrier function of the epithelium and both claudins-3 and -4 were localized to the tight junction.…”

“…It is clear from studies of the effects of prolactin and dexamethasone on claudin distribution in isolated mammary epithelial cells [64], that claudins-3 and -4 respond to hormones in the same manner as secreted proteins like casein, but the detailed mechanisms of the hormone effects are not known.What is the structure and function of the puncta containing non-junctional claudins? A start to answering this question would be to analyze the proteins with which the claudins interact, possibly using the biotin ligase technology so effectively utilized by the Anderson laboratory in MDCK cells [39].…”

Low‐quality rice straw forage increases the permeability of mammary epithelial tight junctions in lactating dairy cows

“…Similarly, when cows were fed a nutrient‐restricted diet, they had higher permeability in the tight junctions of mammary glands . Other studies suggest that leaky tight junctions in the mammary gland can be repaired by the injection of hormones, such as cortisol or prolactin, through increasing metabolic glucose availability . In our previous study, we observed that the milk of rice straw‐fed cows had a higher Na + concentration than that of alfalfa‐fed cows, and there was a deficiency of metabolic glucose supply in rice straw‐based diet .…”

“…6 Other studies suggest that leaky tight junctions in the mammary gland can be repaired by the injection of hormones, such as cortisol or prolactin, through increasing metabolic glucose availability. 7 In our previous study, we observed that the milk of rice straw-fed cows had a higher Na + concentration than that of alfalfa-fed cows, and there was a deficiency of metabolic glucose supply in rice straw-based diet. 3,8 Thus, we hypothesized that low-quality forage-based diets may increase the permeability of mammary epithelial tight junctions by affecting mammary epithelial cell proliferation/apoptosis.…”

Oxytocin injections in the postpartal period affect mammary tight junctions in sows

“…Many factors, both local and systemic, can influence the status of mammary tight junctions. Numerous hormones, such as prolactin, progesterone, and glucocorticoids, can play a role in the regulation of tight junctions, but OXY is the hormone harboring the most drastic effects (Nguyen and Neville, 1998;Kobayashi et al, 2016). Large doses of OXY were shown to alter milk composition in a fashion consistent with an increase in permeability of tight junctions.…”