Role of Hormones in the Regulation of RACK1 Expression as a Signaling Checkpoint in Immunosenescence

Abstract

Abstract:Immunosenescence defines the decline in immune function that occurs with aging. This has been associated, at least in part, with defective cellular signaling via protein kinase C (PKC) signal transduction pathways. Our data suggest reduced PKC activation and consequently reduced response to lipopolysaccharide (LPS) stimulation and cytokine release. The lack of PKC activation seems to be dependent on the reduced expression of the receptor for activated C kinase 1 (RACK1), a scaffolding protein involved in multiple signal transduction cascades. The defective expression of RACK1 may be dependent on age-related alteration of the balance between the adrenal hormones cortisol and dehydroepiandrosterone (DHEA). DHEA levels reduce with aging, while cortisol levels remain substantially unchanged, resulting in an overall increase in the cortisol:DHEA ratio. These hormonal changes are significant in the context of RACK1 expression and signaling function because DHEA administration in vivo and in vitro can restore the levels of RACK1 and the function of the PKC signaling cascade in aged animals and in human cells. In contrast, there is evidence that cortisol can act as a negative transcriptional regulator of RACK1 expression. The rack1 gene promoter contains a glucocorticoid responsive element that is also involved in androgen signaling. Furthermore DHEA may have an indirect influence on the post-transcriptional regulation of the functions of the glucocorticoid receptor. In this review, we will examine the role of the hormonal regulation of rack1 gene transcriptional regulation and the consequences on signaling and function in immune cells and immunosenescence.

Oxidative-Inflammatory Stress in Immune Cells from Adult Mice with Premature Aging

“…Nevertheless, the appearance of age-related changes in the immune system can be modulated. In fact, several potential interventions, such as hormonal replacement therapies, physical activity, cytokine therapy, and/or altering microbiota profiles, have been reported as capable of attenuating immunosenescence and preserving health [25,26,27]. However, other situations, such as an inadequate stress response, can contribute to the age-related changes that the immune system suffers, thus increasing the probability of early death.…”

Endocrine-Disrupting Chemicals’ (EDCs) Effects on Tumour Microenvironment and Cancer Progression: Emerging Contribution of RACK1

“…Literature data report that DHEA can restore the age-associated decline of RACK-1 expression and immune functions both in vitro and in vivo [233][234][235]. The key mechanism of DHEA positive effect on RACK1 expression and monocyte activation is the conversion of DHEA to active androgens, which act via AR, justifying DHEA anti-glucocorticoid action on RACK1 expression described in the immune context [20,227]. Indeed, the bioinformatics analysis of the RACK1 promoter revealed the presence of a glucocorticoid response element (GRE) consensus sequence identified at the nucleotide position −186/−165 relative to the transcription start site [20].…”

“…The key mechanism of DHEA positive effect on RACK1 expression and monocyte activation is the conversion of DHEA to active androgens, which act via AR, justifying DHEA anti-glucocorticoid action on RACK1 expression described in the immune context [20,227]. Indeed, the bioinformatics analysis of the RACK1 promoter revealed the presence of a glucocorticoid response element (GRE) consensus sequence identified at the nucleotide position −186/−165 relative to the transcription start site [20]. Accordingly, physiological concentrations of cortisol can down-regulate RACK1 expression by inhibiting its gene promoter activity [227].…”

“…The role of EDCs in modulating the tumour microenvironment has not been elucidated, but is of pivotal interest. In this regard, the scaffold protein Receptor for Activated C Kinase 1 (RACK1) is an EDC target in the immune context [17][18][19][20] and an important molecular player for cancer progression (reviewed in [21]). Therefore, EDCs-mediated RACK1 regulation in both contexts could be central to understand the role of endocrine-mediated microenvironment regulation and to link innate immune activation with cancer progression through RACK1.…”

PLCE1Promotes the Invasion and Migration of Esophageal Cancer Cells by Up-Regulating the PKCα/NF-κB Pathway

“… 10 Interestingly, Zhao, et al 11 found that protein kinase C (PKC) could activate multiple signaling pathways, including NF-κB and that it could be activated indirectly by phospholipase C: PKC plays an important role in cell proliferation, differentiation, apoptosis, hormone secretion, and gene expression, and PKC is a key link in a series of cell signal transduction pathways. 12 …”