Mechanisms Underlying the Diminished Sensitivity to Prolactin Negative Feedback during Lactation: Reduced STAT5 Signaling and Up-Regulation of Cytokine-Inducible SH2 Domain-Containing Protein (CIS) Expression in Tuberoinfundibular Dopaminergic Neurons

Abstract

Hyperprolactinaemia during lactation is a consequence of the sucking stimulus and in part due to reduced prolactin (PRL) negative feedback. To date, the mechanisms involved in this diminished sensitivity to PRL feedback are unknown but may involve changes in PRL signal transduction within tuberoinfundibular dopaminergic (TIDA) neurons. Therefore, we investigated signal transducers and activators of transcription (STAT) 5 signaling in the TIDA neurons of lactating rats. Dual-label confocal immunofluorescence studies were used to determine the intracellular distribution of STAT5 within TIDA neurons in the dorsomedial arcuate nucleus. In lactating rats with pups removed for 16 h, injection of ovine PRL significantly (P < 0.05) increased the STAT5 nuclear/cytoplasmic ratio compared with vehicle-treated mothers. In contrast, ovine PRL injection did not increase the STAT5 nuclear/cytoplasmic ratio in lactating mothers with pups, demonstrating that PRL signal transduction through STAT5 is reduced in TIDA neurons in the presence of pups. To investigate possible mechanisms involved in reduced PRL signaling, we examined the expression of suppressors of cytokine signaling (SOCS) proteins. Northern analysis on whole hypothalamus showed that CIS (cytokine-inducible SH2 domain-containing protein), but not SOCS1 or SOCS3, mRNA expression was significantly (P < 0.01) up-regulated in suckled lactating rats. Semiquantitative RT-PCR on arcuate nucleus micropunches also showed up-regulation of CIS transcripts. Immunofluorescence studies demonstrated that CIS is expressed in all TIDA neurons in the dorsomedial arcuate nucleus, and the intensity of CIS staining in these neurons is significantly (P < 0.05) increased in lactating rats with sucking pups. Together, these results support the hypothesis that loss of sensitivity to PRL-negative feedback during lactation is a result of increased CIS expression in TIDA neurons.

Identification of salsolinol in the mediobasal hypothalamus of lactating ewes and its relation to suckling-induced prolactin and GH release

“…This last molecule is a member of the family of proteins known to negatively regulate prolactin signalling. This study demonstrated that in lactating rats, CIS level in dopaminergic, neurons increased in the presence of suckling pups (Anderson et al 2006).…”

“…Prolactin through binding to its receptors specifically activates signal transducer and activator of transcription 5b (STAT5b) in dopaminergic neurons, leading to the increased expression and activity of tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis (Ma et al 2005a,b). During lactation, dopaminergic neurons are unresponsive to prolactin (Arbogast & Voogt 1996), which results from reduced STAT5b signalling due to increased expression of cytokine-inducible SH2 domaincontaining protein (CIS; Anderson et al 2006). This last molecule is a member of the family of proteins known to negatively regulate prolactin signalling.…”

“…It is accepted that the hypothalamic neuroendocrine dopaminergic (NEDA) system exerts a dominant and inhibitory effect on prolactin and that prolactin acts in a short-loop feedback manner to regulate its own secretion by stimulating the NEDA system (Freeman et al 2000). Studies on rodents showed that during late pregnancy, the NEDA system had a reduced ability to respond to prolactin (Grattan & Averill 1995, Andrews et al 2001 and that this impaired negative feedback continued into lactation (Arbogast & Voogt 1996, Anderson et al 2006, allowing the maintenance of increased prolactin secretion to promote lactogenesis. Increased secretion of prolactin is also responsible for the stimulation of maternal behaviour and may contribute to the suppression of the stress response during lactation (Grattan 2002).…”

Deficiency of prolactin‐inducible protein leads to impaired Th1 immune response and susceptibility to Leishmania major in mice

“…The function of PIP is not known, but it is suspected to play a role in host defense against pathogens [1][2][3][4][5][6] because it is expressed in tissues strategically located at several Correspondence: Dr. Jude E. Uzonna e-mail: jude.uzonna@med.umanitoba.ca ports of pathogen entry, including the skin, eyes, and mouth [7]. Although a definitive evidence showing a role for PIP in host immunity is lacking, its ability to potentially bind with several important host molecules including CD4 + T-cell receptor, IgG, actin, zinc α2-glycoprotein, fibronectin, and enamel pellicle suggests it may have important biological functions [8][9][10][11][12][13]. Indeed, it has been shown that PIP is a ligand of the CD4 molecule and a potent inhibitor of * These authors contributed equally to this manuscript.…”

Prolactin and the physiological regulation of its secretion. A review

“…Studies on rats have shown that the dopaminergic system in the hypothalamus during late pregnancy has reduced ability to respond to PRL (Grattan and Averill, 1995;Andrews et al, 2001) and that this impaired negative feedback is continued into lactation (Arbogast and Voogt, 1998;Anderson et al, 2006), allowing the maintenance of increased PRL secretion to promote lactogenesis.…”