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Multiple Signal Integration by the Glucocorticoid Receptor

  • Author(s): Pantoja, Carlos J.
  • Advisor(s): Yamamoto, Keith R
  • et al.
Abstract

Glucocorticoids are steroid hormones that control multiple aspects of mammalian physiology. Glucocorticoids act through the glucocorticoid receptor (GR), a ligand-regulated transcriptional regulatory factor that is ubiquitously expressed. It is still unknown how the structurally simple glucocorticoid hormones generate diverse physiological outputs across multiple target tissues. To examine this question we characterized the activities of synthetic glucocorticoid ligands across a panel of GR-induced biological activity profiles. Our studies demonstrated that ligand structure is an important determinant of GR function. We found that arylpyrazole glucocorticoid compounds supported GR activities related to adipogenesis, inhibition of cell proliferation, inhibition of asthma marker gene expression and anti-inflammation, but did not inhibit osteoblast differentiation in cell culture. Additionally, arylpyrazole GR ligands displayed gene-specific transcriptional effects.

To investigate the therapeutic effects of glucocorticoids in lung epithelial cells during asthma treatment we developed a cell culture-based model for gene regulation. We found that dexamethasone and budesonide repressed the IL-13-induced asthma marker genes POSTN, SERPINB2 and CLCA1 in primary human bronchoepithelial cells. We found that the kinetics of regulation of asthma marker genes was slower when compared than that of other IL-13 regulated genes. In addition, the gene SERPINB2 was regulated by dexamethasone as part of a cluster of SERPINB genes that were all also induced by IL-13 treatment.

Finally, we discovered that glucocorticoids induce a novel state during adipogenesis in cell culture. Dex-primed preadipocytes are an intermediate cellular state between preadipocytes and adipocytes that differentiate into adipocytes when exposed to cAMP signaling. Importantly, we found that the mode of differentiation influences the metabolic properties of adipocytes. In summary, our results suggest that the diversity of glucocorticoid activities is generated by the combined actions of signals induced by the ligand itself, the cellular context and additional signaling pathways that affect glucocorticoid activity and the associated phenotypes.

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