Hypothalamic-pituitary cytokine network.
Cytokines expressed in the brain and involved in regulating the hypothalamus-pituitary-adrenal (HPA) axis contribute to the neuroendocrine interface. Leukemia inhibitory factor (LIF) and LIF receptors are expressed in human pituitary cells and murine hypothalamus and pituitary. LIF potently induces pituitary proopiomelanocortin (POMC) gene transcription and ACTH secretion and potentiates CRH induction of POMC. In vivo, LIF, along with CRH, enhances POMC expression and ACTH secretion in response to emotional and inflammatory stress. To further elucidate specific roles for both CRH and LIF in activating the inflammatory HPA response, double-knockout mice (CRH/LIFKO) were generated by breeding the null mutants for each respective single gene. Inflammation produced by ip injection of lipopolysaccharide (1 microg/mouse) to double CRH and LIF-deficient mice elicited pituitary POMC induction similar to wild type and markedly higher than in single null animals (P<0.0.01). Double-knockout mice also demonstrated robust corticosterone response to inflammation. High pituitary POMC mRNA levels may reflect abundant TNFalpha, IL-1beta, and IL-6 activation observed in the hypothalamus and pituitary of these animals. Our results suggest that increased central proinflammatory cytokine expression can compensate for the impaired HPA axis function and activates inflammatory ACTH and corticosterone responses in mice-deficient in both CRH and LIF.
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology*; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D007375:Interleukin-1 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000276:immunology*; D011506:Proteins / Q000235:genetics; D018121:Receptors, Cytokine / Q000378:metabolism; D053606:Receptors, OSM-LIF; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D011506:Proteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone