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Published on: February 21, 2018
Hypothalamic and pituitary leukemia inhibitory factor gene expression in vivo: a novel endotoxin-inducible
1Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, Los Angeles, California 90048-1865, USA.
Insights
Leukemia inhibitory factor (LIF) and its receptor are present in the mouse brain and are upregulated by endotoxin. This suggests a role for LIF in the neuroendocrine response to inflammation.
Area of Science:
- Neuroendocrinology
- Immunology
- Molecular Biology
Background:
- Leukemia inhibitory factor (LIF) has been shown to induce POMC transcription in human pituitary cells.
- The role of LIF in the central nervous system's response to immune signals is not fully understood.
Purpose of the Study:
- To investigate the constitutive and endotoxin-induced expression of LIF and LIF-receptor (LIF-R) in the mouse hypothalamus and pituitary.
- To elucidate the role of alternatively spliced LIF transcripts in the neuroendocrine response to lipopolysaccharide (LPS).
Main Methods:
- Qualitative and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze LIF and LIF-R expression.
- Mice were administered LPS to induce an inflammatory response.
- Expression levels and alternative splicing of LIF mRNA were quantified.
Main Results:
- LIF and LIF-R are constitutively expressed in the normal mouse hypothalamus and pituitary.
- LPS administration significantly induced LIF and LIF-R expression in both tissues.
- LPS induced both diffusible and matrix-associated LIF mRNA transcripts, unlike the constitutive expression.
- Hypothalamic LIF mRNA increased at 30 min post-LPS, while pituitary LIF and peripheral ACTH peaked at 60 min.
Conclusions:
- Mouse LIF (mLIF) is a novel LPS-inducible proinflammatory neuroendocrine cytokine.
- Alternatively spliced, diffusible LIF may act in a paracrine manner to enhance pituitary ACTH secretion, potentially synergizing with hypothalamic CRH.
- This highlights a mechanism for central nervous system cytokine involvement in immune signal responses.
Abstract:
We have recently shown expression of leukemia inhibitory factor (LIF) in human fetal pituitary tissue and its in vitro induction of POMC transcription. We now use qualitative and semiquantitative RT-PCR to demonstrate that LIF and LIF-receptor (LIF-R) are constitutively expressed in the normal mouse hypothalamus and pituitary. Hypothalamic and pituitary LIF and LIF-R are significantly induced (up to 6- and 4-fold, respectively) in vivo in response to lipopolysaccharide endotoxin (LPS) administered to B6D2F1 and C57BL/6 mice. In contrast to the nearly exclusive expression of matrix-associated LIF messenger RNA (mRNA) in control hypothalamus and pituitary, both diffusible and matrix-associated LIF mRNA alternate transcripts are induced by LPS. Furthermore, the time course of peripheral ACTH-response to LPS peaks at 60 min, whereas hypothalamic LIF mRNA increase occurs at 30 min and pituitary LIF induction occurs at 60 min. These results show that mLIF is a novel LPS-inducible proinflammatory neuroendocrine cytokine and the alternatively spliced diffusible LIF may play a paracrine role in activating pituitary ACTH secretion in synergy with hypothalamic CRH, implying a mechanism for central nervous system cytokine responses to immune signals.
