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Cytokine Regulation of the Rat Proopiomelanocortin Gene Expression in AtT-20 Cells

First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya 466, Japan

Although cytokines are known to be involved in the regulation of ACTH secretion, their effects, along with the molecular mechanisms, on POMC gene expression are not thoroughly characterized. In this study we examined the effects of representative cytokines on transcription of the POMC gene in corticotrophs in vitro using AtT20PL, a clone of the AtT20 cell line stably transfected with approximately 0.7 kilobase of the rat POMC 5'-promoter-luciferase fusion gene. In each experiment, cells were incubated with the cytokine tested, and the changes in POMC 5'-promoter activity were determined by a luciferase assay. The results showed that interleukin-1ß (IL-1ß) stimulated promoter activity in a biphasic manner [weak short term effects (2–3 h) followed by potent long term effects (>12–16 h)]. Tumor necrosis factor- had similar effects, but much less potency. IL-6 showed a profound stimulatory, but only a long term (>20 h), effect. IL-2 did not influence POMC expression. In contrast, interferon- (IFN) and IFN- showed acute stimulatory effects (4 h) followed by marked inhibitory effects (>8 h). Although the acute effects of IL-1ß, IL-6, and tumor necrosis factor- alone were minimal, they significantly potentiated the stimulatory effect of CRH on POMC expression. Finally, pretreatment of the cells with a broad spectrum tyrosine kinase inhibitor, genistein, abolished or significantly diminished the effects of all cytokines except IFNs. Our results suggest that 1) each cytokine tested has a distinct effect on POMC gene expression; 2) there are positive cross-talk effects between CRH and cytokines at the corticotroph level; and 3) tyrosine phosphorylation cascades are involved in the intracellular signaling mechanisms of some cytokines.

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