Suppression of prolactin-induced signal transducer and activator of transcription 5b signaling and induction of suppressors of cytokine signaling messenger ribonucleic acid in the hypothalamic arcuate nucleus of the rat during late pregnancy and lactation.
During late pregnancy and lactation, the tuberoinfundibular dopamine (TIDA) neurons that regulate prolactin secretion by negative feedback become less able to produce dopamine in response to prolactin, leading to hyperprolactinemia. Because prolactin-induced activation of dopamine synthesis in these neurons requires the Janus kinase/signal transducer and activator of transcription 5b (STAT5b) signaling pathway, we investigated whether prolactin-induced STAT5b signaling is reduced during lactation and whether induction of suppressors of cytokine signaling (SOCS) mRNAs occur at this time and in late pregnancy. During lactation, the ability of exogenous prolactin to induce STAT5 phosphorylation and STAT5b nuclear translocation was markedly reduced when compared with diestrous rats. In nonpregnant female rats, acute treatment with ovine prolactin markedly increased levels of SOCS-1 and -3 and cytokine-inducible SH2-containing protein mRNA in arcuate nucleus micropunches. On gestation d 22, SOCS-1 and SOCS-3 mRNA levels were 10-fold that on G20. SOCS-1 and -3 and cytokine-inducible SH2-containing protein mRNA levels were also elevated on lactation d 7. At these times, dopaminergic activity was decreased and the rats were hyperprolactinemic. The high levels of SOCS mRNA were prevented by bromocriptine pretreatment (gestation d 22) or pup removal (lactation d 7), which suppressed circulating prolactin to basal levels. These results demonstrate that around the end of pregnancy, prolactin loses the ability to activate STAT5b, associated with an increase in SOCS mRNAs. The loss of this stimulating pathway may underlie the reduced tuberoinfundibular dopamine neuron dopamine output and hyperprolactinemia that characterizes late pregnancy and lactation. The high maternal levels of SOCS mRNAs appear to be dependent on prolactin, presumably acting through an alternative signaling pathway to STAT5b.
Anderson
Greg M
GM
Centre for Neuroendocrinology and Department of Anatomy and Structural Biology, University of Otago School of Medical Sciences, Dunedin 9054, New Zealand. greg.anderson@anatomy.otago.ac.nz
Beijer
Paulien
P
Bang
Angela S
AS
Fenwick
Mark A
MA
Bunn
Stephen J
SJ
Grattan
David R
DR
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D030762:Estrous Cycle / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007774:Lactation / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010477:Perfusion; D011247:Pregnancy / Q000502:physiology*; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis* / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018076:DNA, Complementary; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; D050826:Suppressor of Cytokine Signaling Proteins; D011388:Prolactin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine