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Interleukin-11 Stimulates Proopiomelanocortin Gene Expression and Adrenocorticotropin Secretion in Corticotroph Cells: Evidence for a Redundant Cytokine Network in the Hypothalamo-Pituitary-Adrenal Axis¹

Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Dr. Shlomo Melmed, Academic Affairs, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu

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 of luciferase 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.

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