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¹ Department of Neuroendocrinology² , Department of Molecular Neurogenetics³ Department of Inflammatory Disorders of the CNS at the Max Planck Institute of Psychiatry, Munich 80804, Germany⁴ Department of Neurosurgery, University of Erlangen, Erlangen 91054, Germany⁵ Affectis Pharmaceuticals, Munich 82152, Germany⁶ Laboratorio de Fisiología y Biología Molecular, University of Buenos Aires and CONICET, Buenos Aires 1428, Argentina

(Correspondence should be addressed to M Labeur; Email: labeur{at}mpipsykl.mpg.de)

Interferon- (IFNG) is a cytokine that exerts potent antiproliferative and tumoricidal effects in a variety of cancers. Moreover, IFNG modulates normal pituitary hormone secretion, and was shown to inhibit the expression of the ACTH precursor POMC in murine ACTH-secreting AtT-2010/21/2008 tumor cells. We have studied the functional role of IFNG on pituitary tumor cells, focusing on the involvement of IFNG in the molecular events leading to the control of POMC transcriptional repression. Herein, it is shown that IFNG inhibits AtT-20 tumor cell proliferation without inducing apoptosis. Unexpectedly, an activated janus kinases–signal transducer and activator of transcription (JAK–STAT1) cascade is required for IFNG inhibitory action on POMC promoter activity. Factor-kappa B (NF-B) is necessary for the inhibitory action of IFNG on Pomc transcription, since loss of NF-B activity with IB super-repressor abolishes this effect. In addition, 1 and 2 IFNG receptor immunoreactivity was detected in human corticotropinoma cells. Interestingly, IFNG inhibits ACTH production from these cells in primary cell culture, without affecting basal ACTH biosynthesis in normal non-tumoral pituitary cells. In conclusion, our data show for the first time that POMC transcription can be negatively regulated by a JAK–STAT1 and NF-B-dependent pathway.

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