Abstract
We have shown that leukemia inhibitory factor (LIF) and suppressor of cytokine signaling (SOCS)-3 are expressed in the hypothalamus and pituitary and that LIF induces proopiomelanocortin (POMC) and ACTH, whereas SOCS-3 abrogates corticotroph POMC gene transcription and ACTH secretion. Here, we determined the role of pituitary LIF and SOCS-3 in regulating hypothalamo-pituitary-adrenal (HPA) axis inflammatory responses. Murine pituitary LIF expression was induced up to eightfold after intraperitoneal injection of lipopolysaccharide or tumor necrosis factor-alpha, concordant with elevated plasma levels of ACTH and corticosterone. In LIF knockout (LIFKO) mice, induction of both ACTH and corticosterone were attenuated. LIF deletion was associated with elevated (P < 0.05) levels of pituitary TNF-alpha, interleukin (IL)-1beta, and IL-6 mRNA and cytokine-inducible pituitary SOCS-3 expression. Abrogation of the HPA axis stress response and higher pituitary levels of proinflammatory cytokines observed in LIFKO mice resulted in a stronger inflammatory process, as evidenced by elevated erythrocyte sedimentation rate and increased serum amyloid A levels (P < 0.05). The results indicate that, although LIF induces ACTH, SOCS-3 acts to counterregulate the HPA axis response to inflammation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acute Disease
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Adrenocorticotropic Hormone / blood*
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Animals
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Corticosterone / blood
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Cytokines / genetics
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Female
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Gene Expression / immunology
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Growth Inhibitors / genetics
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Growth Inhibitors / metabolism*
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Hypothalamo-Hypophyseal System / immunology
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Hypothalamo-Hypophyseal System / metabolism*
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Inflammation / chemically induced
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Inflammation / immunology
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Inflammation / metabolism
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Interleukin-6*
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Leukemia Inhibitory Factor
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Lipopolysaccharides
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Lymphokines / genetics
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Lymphokines / metabolism*
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Male
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Mice
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Mice, Knockout
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Neuroimmunomodulation / physiology
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Pituitary-Adrenal System / immunology
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Pituitary-Adrenal System / metabolism*
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Pro-Opiomelanocortin / genetics
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Proteins / genetics
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Proteins / metabolism*
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RNA, Messenger / analysis
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Repressor Proteins*
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors*
Substances
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Cytokines
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Growth Inhibitors
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Interleukin-6
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Leukemia Inhibitory Factor
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Lif protein, mouse
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Lipopolysaccharides
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Lymphokines
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Proteins
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RNA, Messenger
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Repressor Proteins
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors
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Pro-Opiomelanocortin
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Adrenocorticotropic Hormone
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Corticosterone