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

Authors: Wang, Thomas - Tom; Pham, Quynhchi; KIM, YOUNG - National Cancer Institute (NCI, NIH)

Submitted to: International Journal of Molecular Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/21/2018
Publication Date: 2/18/2018
Citation: Wang, T.T., Pham, Q., Kim, Y.S. 2018. 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. International Journal of Molecular Sciences. 19(2):pii:E339. https://doi.org/10.3390/ijms19020339.
DOI: https://doi.org/10.3390/ijms19020339

Interpretive Summary: Indole-3-carbinol (I3C) and its dimer diindolylmethane (DIM) are bioactive metabolites of a glucosinolate, glucobrassicin found in cruciferous vegetables. Both I3C and DIM have been reported to possess anti-apoptotic, anti-proliferative and anti-carcinogenic properties via the modulation of immune pathways. However, results from these studies remain inconclusive since they lack thorough evaluation of these bioactive’s physiological versus pharmacological effects. The current study tests the hypothesis that the diet-derived cancer protective compounds, indole-3-carbinol (I3C) and 3, 3’-diindolylmethane (DIM), affect tumor microenvironment by the regulation of interleukin-1 beta (IL-1 beta) expression in monocytes and macrophages. We also investigated the potential for I3C and DIM to act as mediators via the aryl hydrocarbon (AHR)-dependent pathway, involving the signaling lymphocyte activation molecule (SLAM) family protein CD84. The effect of I3C and DIM was examined using the human THP-1 cell in its un-differentiated (monocyte) and differentiated (macrophage) state. Lipopolysaccharide (LPS) was used to simulate inflammation and IL-1 beta was used as an efficacies end point. SiRNA against AHR was used to affirm the role of AHR. We observed that I3C and DIM differentially regulated the function of both monocytes and macrophages. Importantly, I3C and DIM inhibited LPS induction of IL-1 beta mRNA and protein in the monocyte form, but not the macrophage form of THP-1. CD84 mRNA, but not protein, was inhibited by I3C and DIM. SiRNA knockdown experiments of AHR confirmed that the inhibitory effects of I3C and DIM on IL-1 beta are regulated through AHR-mediated pathway. Hence, diet-derived cancer protective compounds can modulate tumor microenvironment through cross-talk between AHR and inflammation-mediated pathways.

Technical Abstract: 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 the regulation of interleukin-1 beta (IL-1 beta) expression in monocytes and macrophages. We also investigated the potential for I3C and DIM to act as mediators via the aryl hydrocarbon (AHR)-dependent pathway, involving the signaling lymphocyte activation molecule (SLAM) family protein CD84. The effect of I3C and DIM was examined using the human THP-1 cell in its un-differentiated (monocyte) and differentiated (macrophage) state. Lipopolysaccharide (LPS) was used to simulate inflammation and IL-1 beta was used as the efficacies end point. SiRNA against AHR was used to affirm the role of AHR. We observed that I3C and DIM differentially regulated the function of both monocytes and macrophages. Importantly, I3C and DIM inhibited LPS induction of IL-1 beta mRNA and protein in the monocyte form, but not the macrophage form of THP-1. CD84 mRNA, but not protein, was inhibited by I3C and DIM. SiRNA knockdown experiments of AHR confirmed that the inhibitory effects of I3C and DIM on IL-1 beta are regulated through AHR-mediated pathway. Diet-derived cancer protective compounds can modulate tumor microenvironment through cross-talk between AHR and inflammation-mediated pathways.