Elucidating the Role of CD84 and AHR in Modulation of LPS-Induced Cytokines Production by Cruciferous Vegetable-Derived Compounds Indole-3-Carbinol and 3,3′-Diindolylmethane

Modulation of the immune system by cancer protective food bioactives has preventive and therapeutic importance in prostate cancer, but the mechanisms remain largely unclear. The current study tests the hypothesis that the diet-derived cancer protective compounds, indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM), affect the tumor microenvironment by regulation of inflammatory responses in monocytes and macrophages. We also ask whether I3C and DIM act through the aryl hydrocarbon (AHR)-dependent pathway or the signaling lymphocyte activation molecule (SLAM) family protein CD84-mediated pathway. The effect of I3C and DIM was examined using the human THP-1 monocytic cell in its un-differentiated (monocyte) and differentiated (macrophage) state. We observed that I3C and DIM inhibited lipopolysaccharide (LPS) induction of IL-1β mRNA and protein in the monocyte form but not the macrophage form of THP-1. Interestingly, CD84 mRNA but not protein was inhibited by I3C and DIM. AHR siRNA knockdown experiments confirmed that the inhibitory effects of I3C and DIM on IL-1β as well as CD84 mRNA are regulated through AHR-mediated pathways. Additionally, the AHR ligand appeared to differentially regulate other LPS-induced cytokines expression. Hence, cross-talk between AHR and inflammation-mediated pathways, but not CD84-mediated pathways, in monocytes but not macrophages may contribute to the modulation of tumor environments by I3C and DIM in prostate cancer.