1. ¹Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
2. ²Department of Obstetrics and Gynecology, Division of Reproductive Biology, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
3. ³Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: Dr K Kawana, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kkawana-tky@umin.ac.jp

⁴These authors contributed equally to this work.

Received 28 December 2006; Revised 12 March 2008; Accepted 13 March 2008; Published online 15 April 2008.

Abstract

Low-dose prolactin induces proinflammatory responses and antibody production, whereas high-dose prolactin suppresses these responses. Mechanisms for these opposing effects remain incompletely defined. We have previously demonstrated that T-bet, a key transcription factor directing T helper type 1 inflammatory responses, is regulated by female steroid hormones in human mucosal epithelial cells via Stat1 and 5 pathways. T-bet was also modulated in a CD4⁺ T cell line by prolactin exposure. Prolactin rapidly induced T-bet transcription through phosphorylation of JAK2 and Stat5, but not Stat1. Phosphorylated Stat5 then bound to the T-bet regulatory region. These effects were weaker with high-dose prolactin exposures. Upon long-term prolactin exposure, low-dose prolactin induced T-bet expression, whereas high-dose prolactin tended to suppress it. Prolactin induced the suppressors of cytokine signaling (SOCS) 1 and 3 in a dose-dependent manner. With high-dose exposure, this was associated with an inhibition of the phosphorylation of T-bet regulatory region-bound Stat5. Further, the dose-dependent prolactin effects on T-bet expression were confirmed in murine primary CD4⁺ T cells. These data suggest that the divergent immune effects of low- and high-dose prolactin may involve modulation of T-bet and alterations in the balance of the prolactin/JAK2/Stat5 and the prolactin/SOCS1 and 3 pathways.