Abstract

Cortisol, a hormone produced by a hormone produced by the adrenal gland, is responsible for many regulatory functions in the body. Cortisol release is mediated by adrenocorticotrophic hormone, or ACTH, through the hypothalamus-pituitary-adrenal or HPA axis. This HPA axis is the major release pathway used during acute stress, during which the levels of ACTH parallel those of cortisol. However, in states of chronic stress, the level of ACTH drops dramatically, while cortisol remains high. This study focuses on the pathway of cortisol release during these chronic stress states, specifically examining the role of IL-6 with respect to STATs and the Jak/STAT pathway. It has been shown that IL-6 increases cortisol levels, and that IL-6 utilizes the Jak/STAT pathway. Also, the steroidogenic acute regulatory (StAR) promoter contains multiple STAT binding sites. Thus, STATs could be mediating the effects of IL-6 in the chronic release of cortisol by inducing expression of StAR. Experiments were performed to identify whether IL-6 has a direct effect on StAR promoter activity, StAR mRNA and StAR protein levels. Electromobility Shift Assays (EMSA) were performed to show that STATs bind to the full STAT site within the StAR promoter region. Various experiments were also carried out in the presence of IL-6 alone or, congruently with either a Jak (AG490) or STAT3 (Piceatannol) inhibitor, to show the effects of STATs and the Jak/STAT pathway on StAR. Luciferase assays were performed in order to observe the effects on induction of the StAR promoter. RT-PCR and western blots were also performed to observe the effect of Jak/STAT inhibition on both StAR mRNA levels and StAR protein levels. These experiments showed a marked decrease in the IL-6-stimulated StAR promoter activity, mRNA and protein expression when treated with wither Jak or STAT inhibitor. Therefore, IL-6 regulates expression of StAR through utilization of the Jak/STAT pathway; which phosphorylates and subsequently dimerizes STAT, allowing STAT to translocate to the nucleus and bind to the StAR promoter, thus increasing StAR expression and thereby inducing synthesis of cortisol.

Degree

MS

College and Department

Life Sciences; Physiology and Developmental Biology

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2007-03-21

Document Type

Thesis

Handle

http://hdl.lib.byu.edu/1877/etd1781

Keywords

StAR, Jak, STAT, Interleukin-6, steroid hormone production, adrenal gland

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