Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing

Bousquet, Corinne; Zatelli, Maria Chiara; Melmed, Shlomo

doi:10.1172/jci11182

Cited by 97 publications

(91 citation statements)

References 40 publications

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“…The signal, mediated by various cytokines, is integrated at the hypothalamic level, and then the CRH/vasopressin-ACTH-cortisol pathway is activated [8,9]. In addition, the effects of cytokines on pituitary cells have also been reported [10,11]. In this study, we showed the expression of a variety of TLR subtype mRNAs in the AtT20 corticotroph cell line.…”

Section: Discussionmentioning

confidence: 56%

Lipopolysaccharide Stimulates Proopiomelanocortin Gene Expression in AtT20 Corticotroph Cells

et al. 2008

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Abstract. While lipopolysaccharides (LPS) are known to activate the hypothalamo-pituitary-adrenal axis, their direct effects on proopiomelanocortin (POMC) and adrenocorticotropin (ACTH) expression at the pituitary level through Tolllike receptors (TLRs) remain unclear. In this study, we examined the effects of LPS on ACTH secretion and the transcription of the POMC gene in the AtT20 mouse pituitary corticotroph cell line. RT-PCR analysis showed that TLR1-4 and 6 subtype mRNAs were expressed in AtT20 cells. When the cells were treated with LPS, a significant increase in the 5'-promoter activity of POMC gene was observed at 24 h, without any stimulatory effect on ACTH secretion. LPS also stimulated the expression of c-Fos gene and protein, and AP1-, but not NF-κB-, mediated transcription. Overall, our data show the expression of TLRs in the pituitary corticotroph cells, and suggest the direct stimulatory effect of LPS on POMC gene expression via TLR (probably TLR4), although the intracellular signaling pathways in the corticotroph may be different from those in immune cells.

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Section: Discussionmentioning

confidence: 56%

Lipopolysaccharide Stimulates Proopiomelanocortin Gene Expression in AtT20 Corticotroph Cells

et al. 2008

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“…Physiologically, leptin signaling up-regulates anorexogenic neuropeptides, including ␣-melanocyte-stimulating hormone, a cleavage product of POMC, which functions to inhibit food intake mainly through the G protein-coupled melanocortin-4 receptor (MC4R) (37). POMC was suggested to be a direct STAT3 downstream target gene (38). In both WT and leptinsignaling mutants, one i.p.…”

Section: Resultsmentioning

confidence: 99%

Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation

Gao

Wolfgang

Neschen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

357

239

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Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron͞glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3 N؊/؊ ). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3͞4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3 N؊/؊ mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db͞db and ob͞ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction. Signal transducer and activator of transcription (STAT) proteins are a group of cytokine-activated signaling molecules that can directly bind to DNA and activate or repress transcription of target genes. A myriad of cytokines activate STAT proteins through receptor-associated kinases. Activation of STATs occurs through tyrosine phosphorylation that is required for SH2 domain-mediated dimerization and DNA binding. Most STAT proteins have specific effects, but STAT3, the most ancient STAT, is broadly expressed and activated by a diverse array of cytokines and stresses (1-3). It was initially described as an acute phase protein involved in various biological and pathological processes. STAT3 deletion causes embryonic lethality before gastrulation via an unknown mechanism (4). STAT3 has unusually pleiotropic effects regulating murine embryonic stem cell maintenance (5), macrophage function (6, 7), immune regulation (8), and peripheral neuron survival after axotomy (9, 10) among others.In the CNS, STAT3 is expressed during embryonic development, mostly at ventricular areas, where neuronal proliferation and differentiation take place. Consistently, STAT3 is strongly suggested by in vitro studies to play an instructive role in glial and neuron differentiation (11)(12)(13)(14). In adults, STAT3 has long been implicated in the regulation of energy homeostasis through the fat-derived cytokine leptin. Although leptin can activate several STAT proteins, including STAT3, 5, and 6, in vitro (15), only STAT3 is activated in the hypoth...

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“…Dominant negative forms of STAT3 block the action of LIF in the corticotroph, confirming that this mediator is required for LIF's effects (39). The LIF-responsive POMC promoter region has been mapped by deletion analysis and contains two juxtaposed sequences related to STAT3 DNAbinding motif (40). This evidence for STAT3's direct involvement offers a new mechanistic understanding of the stimulation of the HPA axis by gp130 cytokines and suggests an explanation for the synergism between CRH and LIF in regulating ACTH secretion following exposure to cytokines associated with inflammation and stress.…”

Section: Pituitary Functions Of the Gp130 Cytokinesmentioning

confidence: 87%

gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine–neuro-endocrine pathways

Arzt¹

2001

J. Clin. Invest.

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Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing

Cited by 97 publications

References 40 publications

Lipopolysaccharide Stimulates Proopiomelanocortin Gene Expression in AtT20 Corticotroph Cells

Lipopolysaccharide Stimulates Proopiomelanocortin Gene Expression in AtT20 Corticotroph Cells

Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation

gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine–neuro-endocrine pathways

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