Retinoic acid induced cytokines are selectively modulated by liver X receptor activation in zebrafish

•Retinoic acid induces expression of il22 and il17a/f3, while decreases il10 levels.•LXR modulates the expression of specific cytokines induced by RAR activation.•Simultaneous activation of two or more receptors does not impact on the specific receptor activity. Nuclear receptors (NRs) rapidly activate/repress gene expression to detour immune responses and allow tissue adaptation to constant environmental changes. However, the effect of combined NRs in the immune system is often unclear due to the lack of reliable experimental models that recapitulate the complex interaction between NRs in vivo. Here, we used the zebrafish to investigate the immunological outcome of combining the activation of retinoic acid receptor (RAR), liver X receptor (LXR) and the cytoplasmic sensor aryl hydrocarbon receptor (AHR). Although simultaneous activation did not affect the expression of respective bona-fide target genes, RAR-induced il17a/f3 was antagonized by LXR and AHR, whereas il22 was antagonized by AHR but not LXR. In addition, RA decreased il10 expression, which was further decreased by LXR activation. Thus, using combinatorial NR activation in zebrafish larvae, we show that LXR antagonizes the expression of selected RA-induced cytokines and provide a strategy to tailor the cytokine milieu.