title: Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: implications in immunosenescence.
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.
authors.affiliation: Department of Drug Sciences-Pharmacology Section, Center of Excellence in Applied Biology, University of Pavia, Viale Taramelli 14, Pavia, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Buoso
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Molteni
authors.forename: Françoise
authors.initials: F
authors.lastname: Rousset
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology*; D003687:Dehydroepiandrosterone / Q000378:metabolism* / Q000494:pharmacology; D017353:Gene Deletion; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D008156:Luciferases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D003687:Dehydroepiandrosterone; D008156:Luciferases; D006854:Hydrocortisone