Moderate High Temperature Condition Induces the Lactation Capacity of Mammary Epithelial Cells Through Control of STAT3 and STAT5 Signaling

  • Ken Kobayashi
  • Yusaku Tsugami
  • Kota Matsunaga
  • Takahiro Suzuki
  • Takahiro Nishimura


In lactating mammary glands, alveolar mammary epithelial cells (MECs) synthesize and secrete milk components. MECs also form less permeable tight junctions (TJs) to prevent the leakage of milk components. During lactation, MECs are exposed to temperature changes by metabolic heat production and air ambient temperature. In this study, we investigated whether temperature changes influence milk production ability and TJ barriers in MECs by using two lactating culture models. The results showed that 39 °C treatment activated milk production and enhanced the formation of less-permeable TJs. In contrast, 41 °C treatment caused adverse effects on the TJ barrier and cell viability, although the milk production ability of MECs was temporarily up-regulated. MECs cultured at 37 °C showed relatively low milk production ability and high proliferation activity. Furthermore, we investigated three kinds of transcription factors relating to lactogenesis, signal transducer and activator of transcription 5 (STAT5), STAT3 and glucocorticoid receptor (GR). STAT5 signaling was activated at 39 and 41 °C by an increase in total STAT5. However, long-term treatment led to a decrease in total STAT5. STAT3 signaling was inactivated by high temperature treatment through a decrease in total STAT3 and inhibited phosphorylation of STAT3. GR signaling was continuously activated regardless of temperature. These results indicate that a moderate high temperature condition at 39 °C induces a high lactation capacity of MECs through control of STAT5 and STAT3 signaling. In contrast, long-term exposure at 41 °C leads to a decline in milk production capacity by inactivation of STAT5 and a decrease in the total number of MECs.


Mammary epithelial cell Heat stress Milk production 



We are deeply grateful to Prof. Fumio Nakamura, Laboratory of Animal By-Product Science, Research Faculty of Agriculture, Hokkaido University, for fine instruction on immunohistochemistry techniques and useful discussions.

Author Contributions

K.K. conceived the study, participated in the research design and implementation of the study, analyzed and interpreted the data, and drafted the manuscript. T.S. and T.N. participated in the research design and implementation of the study. Y.T. and K.M. performed the experiments and analyzed the data. All authors read and approved the final manuscript.


This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI, 2645044104).

Compliance with Ethical Standards

Competing Interests

The authors declare no competing financial interests.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ken Kobayashi
    • 1
  • Yusaku Tsugami
    • 1
  • Kota Matsunaga
    • 1
  • Takahiro Suzuki
    • 1
  • Takahiro Nishimura
    • 1
  1. 1.Laboratory of Cell and Tissue Biology, Research Faculty of AgricultureHokkaido UniversitySapporoJapan

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