Transcriptional regulation of Sertoli cell immediate early genes by interleukin-6 and interferon-y is mediated through phosphorylation of STAT-3 and STAT-1 proteins
Jenab,Shirzad; Morris,Patricia L.
Endocrinology 138(7): 2740-2746
Publication date: 1997
The immediate early genes are regulated by a variety of extracellular signals,including pleiotropic cytokines. The effects of the testicular cytokines,interleukin-6 (IL-6) and interferon- (IFN-), on signal transducersand activators of transcription 3 and 1 (STAT-3 and STAT-1) andon c-fos gene expression in primary Sertoli cells are suggestiveof their roles in differential function. Using the tyrosine phosphorylationinhibitor, genistein, and electrophoretic mobility shift assay,we show that IL-6 and IFN- induce nuclear factor STAT-3 andSTAT-1 DNA-binding activity to the sis-inducible element ofc-fos in a genistein-dependent pathway. Quantitative solutionhybridization, Northern blot, and nuclear run-on analysis showthat differential induction of c-fos, junB, and c-myc messengerRNA (mRNA) by these cytokines occur at transcriptional levels.IL-6 stimulates c-fos mRNA levels by 6-fold while increasing junBlevels by 2-fold. IFN- increases c-fos message 2-fold, but hasno effect on junB mRNA levels. Furthermore, genistein treatment blocksthe induction of c-fos and junB gene expression, demonstratingthat tyrosine phosphorylation of STAT proteins is involved inthe cytokine regulation of the Sertoli immediate early genes.H7, a serine/threonine phosphorylation inhibitor, also blocksc-fos gene induction by IL-6 and IFN-, but does not affect theDNA-binding activities of STAT-3 and STAT-1. Finally, IL-6 treatmentof Sertoli cells (3-6 h) increases the amounts of activatingprotein-1 binding to activating protein-1 element and c-myctranscription.