Pituitary Corticotroph SOCS-3: Novel Intracellular Regulation of Leukemia-Inhibitory Factor-Mediated Proopiomelanocortin Gene Expression and Adrenocorticotropin Secretion

Mol Endocrinol. 1998 Jul;12(7):954-61. doi: 10.1210/mend.12.7.0140.

Abstract

As pituitary leukemia-inhibitory factor (LIF) mediates neuroimmune signals to the hypothalamo-pituitary-adrenal axis, we tested the role of intracellular SOCS-3 in corticotroph function. SOCS-3, a cytokine-inducible protein of the suppressor of cytokine signaling (SOCS) family, is expressed in the murine pituitary in vivo. After i.p. injection of LIF (5.0 micrograms/mouse) or interleukin-1 beta (0.1 microgram/mouse) pituitary SOCS-3 mRNA was stimulated 9-fold and 6-fold, respectively. Also, in corticotroph AtT-20 cells LIF and interleukin-1 beta both potently stimulated SOCS-3 mRNA expression. In AtT-20 cells, stable overexpression of SOCS-3 inhibits basal and LIF-stimulated ACTH secretion in comparison to mock-transfected AtT-20 cells (basal: 4426 +/- 118 vs. 4973 +/- 138 pg/ml, P < 0.05; LIF-induced: 5511 +/- 172 vs. 9308 +/- 465 pg/ml, P < 0.001). Stable overexpression of SOCS-3 cDNA in AtT-20 cells also resulted in a significant 50% decrease of LIF-induced POMC mRNA levels (P < 0.05) and POMC promoter activity (P < 0.001), respectively. Western blot analysis revealed an inhibition of LIF-stimulated gp130 and STAT-3 phosphorylation in SOCS-3 overexpressing AtT-20 cells. Thus, SOCS-3 inhibits the Janus kinase (JAK) and signal transducers and activators of transcription (STAT) pathway, which is known to mediate LIF-stimulated ACTH secretion and POMC gene expression. In conclusion, SOCS-3 functions as an intracellular regulator of POMC gene expression and ACTH secretion, acting as a negative feedback mediator of the cytokine-mediated neuro-immuno-endocrine interface.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenocorticotropic Hormone / metabolism*
  • Animals
  • Antigens, CD / metabolism
  • Cell Line
  • Cytokine Receptor gp130
  • DNA-Binding Proteins / metabolism
  • Gene Expression / drug effects*
  • Growth Inhibitors / pharmacology*
  • Hypothalamus / metabolism
  • Interleukin-1 / pharmacology
  • Interleukin-6*
  • Leukemia Inhibitory Factor
  • Lymphokines / pharmacology*
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Pituitary Gland / metabolism*
  • Pro-Opiomelanocortin / genetics*
  • Proteins / genetics
  • Proteins / physiology*
  • RNA, Messenger / metabolism
  • Recombinant Proteins / pharmacology
  • Repressor Proteins*
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism
  • Transcription Factors*
  • Transfection

Substances

  • Antigens, CD
  • DNA-Binding Proteins
  • Growth Inhibitors
  • Il6st protein, mouse
  • Interleukin-1
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • Lymphokines
  • Membrane Glycoproteins
  • Proteins
  • RNA, Messenger
  • Recombinant Proteins
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Cytokine Receptor gp130
  • Pro-Opiomelanocortin
  • Adrenocorticotropic Hormone