Opposing effects of pituitary leukemia inhibitory factor and SOCS-3 on the ACTH axis response to inflammation.
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.
Chesnokova
Vera
V
Cedars-Sinai Research Institute-University of California Los Angeles School of Medicine, Los Angeles, California 90048, USA. chesnokova@cshs.org
Kariagina
Anastasia
A
Melmed
Shlomo
S
D000208:Acute Disease; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006131:Growth Inhibitors / Q000235:genetics / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015213:Neuroimmunomodulation / Q000502:physiology; D010913:Pituitary-Adrenal System / Q000276:immunology / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors
D016207:Cytokines; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008070:Lipopolysaccharides; D008222:Lymphokines; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone