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Pituitary-directed leukemia inhibitory factor transgene causes Cushing's syndrome: neuro-immune-endocrine modulation
H Yano1, C Readhead, M Nakashima
1Department of Medicine, Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, 90048, USA.
Insights
Leukemia inhibitory factor (LIF) influences pituitary development. Overexpression of LIF in mice led to dwarfism, hypogonadism, and Cushingoid features, altering cell differentiation in the pituitary gland.
Area of Science:
- Endocrinology
- Developmental Biology
- Neuroimmunology
Background:
- Leukemia inhibitory factor (LIF) is known to regulate the mature hypothalamic-pituitary-adrenal axis.
- In vitro studies show LIF promotes corticotroph cell proliferation and POMC transcription.
Purpose of the Study:
- To investigate the role of LIF in pituitary development.
- To understand how LIF affects the differentiation of pituitary cell lineages.
Main Methods:
- Generation of transgenic mice with LIF expression driven by the alpha-subunit of glycoprotein hormone (alphaGSU) promoter.
- Analysis of pituitary gland morphology, hormone levels (IGF-I, FSH, cortisol), and cell types in transgenic mice compared to wild type (WT).
Main Results:
- Transgenic mice displayed dwarfism (low IGF-I), hypogonadism (low FSH), and Cushingoid features (elevated cortisol).
- Pituitary glands showed corticotroph hyperplasia, somatotroph and gonadotroph hypoplasia, and Rathke-like cysts.
- Early embryonic overexpression of LIF diverted cell differentiation towards corticotrophs and ciliated epithelium.
Conclusions:
- Inappropriate LIF expression significantly impacts pituitary development and function.
- LIF plays a critical role in terminal differentiation events during pituitary development.
- LIF acts as a key cytokine in neuro-immune interactions affecting the pituitary.
Abstract:
Leukemia inhibitory factor (LIF) regulates the mature hypothalamic-pituitary-adrenal axis in vivo. In vitro, LIF determines corticotroph cell proliferation and induces POMC transcription. To explore LIF action on pituitary development, transgenic mice expressing LIF driven by the pituitary glycoprotein hormone alpha-subunit (alphaGSU) promoter were generated. Transgenic mice exhibited dwarfism with low IGF-I (29 +/- 9 ng/ml vs. wild type (WT) 137 +/- 16 ng/ml; P < 0.001), hypogonadism with low FSH (0.04 +/- 0.023 ng/ml vs. WT 0.63 +/- 0.18 ng/ml; P < 0.001), and Cushingoid features of thin skin and truncal obesity with elevated cortisol levels (86 +/- 22 ng/ml vs. WT 50 +/- 14 ng/ml; P = 0.002). Their pituitary glands showed corticotroph hyperplasia, striking somatotroph and gonadotroph hypoplasia, and multiple Rathke-like cysts lined by ciliated cells. LIF, overexpressed in Rathke's pouch at embryonal day 10, diverts the differentiation stream of hormone-secreting cells toward the corticotroph lineage and ciliated nasopharyngeal-like epithelium. Thus, inappropriate expression of LIF, a neuro-immune interfacing cytokine, plays a key role in the terminal differentiation events of pituitary development and mature pituitary function.
