Testicular receptor-4: Novel regulator of glucocorticoid resistance

Abstract

Context: Glucocorticoids are powerful steroid hormones that regulate development, metabolism, and immune response. However, glucocorticoid unresponsiveness or resistance is observed in the treatment of inflammatory, autoimmune, and lymphoproliferative diseases and significantly limits their efficacy. Objective: In Cushing's disease, although some glucocorticoid-mediated suppression of pituitaryderived ACTH is seen, corticotroph tumors exhibit relative resistance to glucocorticoid action. We previously demonstrated that testicularorphanreceptor 4 (TR4) binds to the pro-opiomelanocortin (POMC) promoter to induce corticotroph tumor POMC expression and ACTH secretion, and we hypothesized that TR4 may interact with glucocorticoid signaling to modulate POMC expression and action. Results: Herewedemonstrate thatTR4abrogates glucocorticoid receptor (GR)- or dexamethasonemediated POMC and activator protein-1 transrepression in both murine and human pituitary corticotrophtumorcells. Co-immunoprecipitation studies indicate thatTR4andGRinteract directly with each other, resulting in TR4-mediated disruption of GR binding to the POMC promoter. Conclusion: These results demonstrate that TR4 binds GR to play an important role in glucocorticoid-directed corticotroph tumor POMC regulation in addition to modulating glucocorticoid actions on other GR targets. Characterization of this pathway may offer important insights into glucocorticoid resistance and may identify a novel approach for the treatment of Cushing's disease and the glucocorticoid-resistant states.