Aging is associated to a decline in immune functions that are in part related to a defective protein kinase C dependent signal transduction machinery. RACK-1 (Receptor for Activated C Kinase 1) is a scaffold protein for different kinases and membrane receptors. We have previously demonstrated, in the elderly, a defective PCKβII (Protein Kinase C βII) translocation related to a decrease in RACK-1 protein expression, which is correlated to the age-associated decline in DHEA (dehydroepiandrosterone) levels. As a consequence of this signal transduction impairment, a significant decrease in immune cells functionality was observed. Furthermore, we could demonstrate that in vivo and in vitro DHEA administration restored RACK-1 level and immune functions, indicating that this hormone behaved as a positive RACK-1 regulator.We have most recently characterized the human GNB2L1 promoter region, coding for RACK-1 protein. Although no direct DHEA responsive elements were found, a glucocorticoid responsive element (GRE) was identified.The purpose of this work was to investigate, in the human pro-myelocytic cell line THP-1, whether physiological cortisol concentrations were able to modulate GNB2L1 promoter activity, RACK-1 transcription as well as cytokine production. As DHEA is endowed of anti-glucocorticoid properties in several cellular systems, and as cortisol:DHEA ratio imbalance is relevant in aging, we also investigated their possible interaction at the RACK-1 expression level.We could demonstrate that cortisol acted in a dose-related manner as a GNB2L1 promoter repressor, reducing RACK-1 mRNA expression and protein level. Probably by interfering with glucocorticoid receptor binding to GRE sequence, prolonged DHEA exposure counteracted cortisol effects, restoring RACK-1 levels and cytokine production, as assessed by LPS-induced TNF-α release.

Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: Implications in immunosenescence / E. Buoso, C. Lanni, E. Molteni, F. Rousset, E. Corsini, M. Racchi. - In: EXPERIMENTAL GERONTOLOGY. - ISSN 0531-5565. - 46:11(2011), pp. 877-883. [10.1016/j.exger.2011.07.007]

Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: Implications in immunosenescence

E. Corsini
Penultimo
;
2011

Abstract

Aging is associated to a decline in immune functions that are in part related to a defective protein kinase C dependent signal transduction machinery. RACK-1 (Receptor for Activated C Kinase 1) is a scaffold protein for different kinases and membrane receptors. We have previously demonstrated, in the elderly, a defective PCKβII (Protein Kinase C βII) translocation related to a decrease in RACK-1 protein expression, which is correlated to the age-associated decline in DHEA (dehydroepiandrosterone) levels. As a consequence of this signal transduction impairment, a significant decrease in immune cells functionality was observed. Furthermore, we could demonstrate that in vivo and in vitro DHEA administration restored RACK-1 level and immune functions, indicating that this hormone behaved as a positive RACK-1 regulator.We have most recently characterized the human GNB2L1 promoter region, coding for RACK-1 protein. Although no direct DHEA responsive elements were found, a glucocorticoid responsive element (GRE) was identified.The purpose of this work was to investigate, in the human pro-myelocytic cell line THP-1, whether physiological cortisol concentrations were able to modulate GNB2L1 promoter activity, RACK-1 transcription as well as cytokine production. As DHEA is endowed of anti-glucocorticoid properties in several cellular systems, and as cortisol:DHEA ratio imbalance is relevant in aging, we also investigated their possible interaction at the RACK-1 expression level.We could demonstrate that cortisol acted in a dose-related manner as a GNB2L1 promoter repressor, reducing RACK-1 mRNA expression and protein level. Probably by interfering with glucocorticoid receptor binding to GRE sequence, prolonged DHEA exposure counteracted cortisol effects, restoring RACK-1 levels and cytokine production, as assessed by LPS-induced TNF-α release.
Cortisol; DHEA; Glucocorticoid response element (GRE); Immunosenescence; RACK-1; Aged; Analysis of Variance; Animals; Blotting, Western; Cell Aging; Cells, Cultured; Dehydroepiandrosterone; Gene Deletion; Humans; Hydrocortisone; Immunity, Cellular; Luciferases; Plasmids; Rats; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface; Transfection; Tumor Necrosis Factor-alpha; Aging; Biochemistry; Cell Biology; Endocrinology; Genetics; Molecular Biology
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/260078
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