Effects of Bisphenols on RACK1 Expression and Their Immunological Implications in THP-1 Cells

Abstract

Receptor for activated C kinase 1 (RACK1) has an important role in immune activation, and is regulated through a balance between glucocorticoid and androgen levels. We have previously demonstrated that RACK1 expression can serve as a marker for evaluation of immunotoxic profiles of hormone-active substances, such as endocrine-disrupting chemicals (EDCs). In this study, we investigated the effects of three bisphenols (BPA, BPAF, BPS) on RACK1 expression and on the innate immune responses in the THP-1 human promyelocytic cell line, a validated model for this investigation. BPA and BPAF reduced RACK1 promoter transcriptional activity, mRNA expression, and protein levels. However, BPS had the opposite effect. As expected, these results on RACK1 were paralleled by lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and tumor necrosis factor-α (TNFα) production. Since BPA and BPAF induced RACK1 expression in the presence of glucocorticoid receptor (GR) antagonist mifepristone, a role of G-protein-coupled estrogen receptor (GPER) has been considered due to their known estrogenic profile. Therefore, additional molecular effects of BPA and BPAF were unmasked after treatment with different inhibitors of well-known pivotal players of GPER-mediated signaling. BPA exerted its effects on RACK1 via NF-κB, as shown using the NF-κB inhibitor BAY11-7085 and NF-κB-specific luciferase reporter assay. Conversely, BPAF induced RACK1 up-regulation via androgen receptor (AR) activation, as confirmed by treatment with AR antagonist flutamide. Indeed, a biased agonism profile for BPA and BPAF for GPER was suggested based on their different binding modes revealed by our molecular docking. Altogether, our data suggest that RACK1 could represent an important target of EDCs and serves as a screening tool for their immunotoxic potential. Furthermore, RACK1 can be exploited to unmask multiple molecular interactions of hormone-active substances to better dissect out their mechanisms of action.

The Labyrinthine Landscape of APP Processing: State of the Art and Possible Novel Soluble APP-Related Molecular Players in Traumatic Brain Injury and Neurodegeneration

“…RACK1 is a scaffold and ribosomal protein involved in a variety of molecular mechanisms, with crucial roles in both physiologic and pathologic conditions. RACK1 exerts its roles in several cellular contexts, including the immune system [ 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 ], cancer cells [ 236 , 237 , 238 , 239 , 240 ], intestinal homeostasis [ 241 , 242 ] and neurons [ 2 , 44 , 141 , 243 , 244 , 245 ]. In this regard, at a neuronal level, RACK1 has been reported to be required for point contact formation, axon outgrowth [ 246 , 247 ], dendritic arborisation [ 248 ], corticogenesis [ 249 ], synaptic plasticity, addiction, learning and memory by regulating N-methyl D-Aspartate (NMDA) receptor function [ 250 ], metabotropic glutamate receptor 1/5 (mGluR1/5)-triggered control of protein synthesis via its association with PKCβII [ 2 ], protection against oxidative stress [ 251 ] and BDNF expression [ 252 , 253 , 254 ].…”

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“…Immunotoxicity is the main and non-negligible side-effect of various anti-tumor treatment strategies ( Buoso et al, 2021 ; Shanti et al, 2021 ). Upon anti-tumor treatment, the number of lymphocytes (especially in peripheral blood) drops sharply in patients ( Fessas et al, 2020 ; Wesley et al, 2021 ).…”

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“…The figure shows that BPA analogues affect both the innate and acquired parts of the immune system. The upward pointing arrows represent an increase in a particular parameter, and the downward pointing arrows represent a decrease (Zhao et al 2017 ; Zhang et al 2021 ; Švajger et al 2016 ; Guo et al 2010 ; Camarca 2016 ; Peillex et al 2021 ; Buoso 2021 ; Malaisé et al 2020a ; Li et al 2018a ; Michałowicz et al 2015 ; Mokra and Michałowicz 2015 ; Mokra et al 2018 ; Buoso et al 2020 ; Chen et al 2018 ). Created with BioRender.com …”