Interleukin-11 stimulates proopiomelanocortin gene expression and adrenocorticotropin secretion in corticotroph cells: evidence for a redundant cytokine network in the hypothalamo-pituitary-adrenal axis.
We recently characterized leukemia inhibitory factor (LIF) as an important modulator of hypothalamo-pituitary-adrenal (HPA) axis activity. We now describe the role of interleukin (IL)-11, another member of the IL-6 cytokine family, in the neuro-immuno-endocrine modulation of the HPA axis. In murine hypothalamus, pituitary and corticotroph AtT-20 cells, IL-11 messenger RNA (mRNA) was detectable by RT-PCR only, whereas IL-11R mRNA transcripts were demonstrated by Northern blot. Using RT-PCR, IL-11 and IL-11R gene expression were also detected in normal human pituitaries, as well as in corticotropic and nonfunctioning pituitary adenomas. Incubation of AtT-20 cells for 24 h with 10(-9) M IL-11 stimulated ACTH secretion 1.4 +/- 0.1-fold (P < 0.01), whereas LIF at the same concentration caused a 1.5 +/- 0.1-fold increase (P < 0.001). POMC mRNA expression was induced by IL-11 (0.5 x 10(-9) M) and LIF (0.5 x 10(-9) M) 1.5 +/- 0.18-fold (P < 0.05) and 1.7 +/- 0.13-fold (P < 0.01), respectively. POMC promoter activity, assayed by a -706/+64 rat POMC promoter-luciferase construct, was stimulated by 0.5 x 10(-9) M IL-11 (1.9 +/- 0.06-fold; P < 0.001) and 5 mM Bu2cAMP (7.1 +/- 0.52-fold, P < 0.001), and combined treatment of IL-11 plus Bu2cAMP caused a synergistic 11.7+/-0.71-fold increase ofluciferase activity (P < 0.001 vs. Bu2cAMP alone). Gene expression of SOCS-3, an intracellular inhibitor of cytokine action, peaked as early as 60 min after incubation with IL-11 (0.5 x 10(-9) M) and was induced 3.5-fold. In comparison to mock-transfected AtT-20 cells (AtT-20M), stable overexpression of SOCS-3 (AtT-20S) resulted in significant inhibition of ACTH secretion induced by IL-11 alone (1.5 +/- 0.09 vs. 1.1 +/- 0.04-fold induction, P < 0.01) and IL-11 plus Bu2cAMP (2.1 +/- 0.21 vs. 1.5 +/- 0.06-fold, P < 0.05), but not by Bu2cAMP alone (1.5 +/- 0.12 vs. 1.4 +/- 0.06). In summary, human and murine pituitary express IL-11 and IL-11R transcripts. In murine corticotroph AtT-20 cells, IL- 11 induces POMC gene transcription and ACTH secretion. IL-11 induction of SOCS-3 indicates an intracellular negative feedback control of cytokine-induced POMC expression and ACTH secretion. Thus, IL-11 regulates the HPA axis similarly to LIF, providing further evidence for a redundant cytokine network in the neuro-immuno-endocrine regulation of the HPA axis.
Auernhammer
C J
CJ
Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
Melmed
S
S
D000236:Adenoma / Q000737:chemistry; D000311:Adrenal Glands / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D005246:Feedback; D015870:Gene Expression; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D017370:Interleukin-11 / Q000235:genetics / Q000494:pharmacology*; D053703:Interleukin-11 Receptor alpha Subunit; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010902:Pituitary Gland / Q000502:physiology*; D010911:Pituitary Neoplasms / Q000737:chemistry; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011506:Proteins / Q000235:genetics / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000235:genetics; D053702:Receptors, Interleukin-11; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
C508428:IL11RA protein, human; C508429:Il11ra1 protein, mouse; C508430:Il11ra1 protein, rat; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D011506:Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone