LAUSR

ABSTRACT We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose‐related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS‐induced IL‐8 and TNF‐&agr; production and proliferation in THP‐1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS‐induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system. HIGHLIGHTSRACK1 expression can be induced by AR agonists with a consequent enhancement of the response to LPS.RACK1 can be negatively modulated by the AR antagonists DDT and its main metabolite p,p′DDE.RACK1 can be a relevant target of EDCs, representing a bridge between the endocrine system and the immune system.