ABSTRACT: Background/Objectives: Aryl hydrocarbon receptor (AHR) ligands are known to suppress antibody production. However, it remains unclear whether this suppression translates into altered antibody-mediated Fcγ receptor signaling in human cells. This study aimed to investigate the effects and mechanisms by which AHR ligands regulate antibody production and antibody-triggered responses in human peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were isolated from blood obtained from healthy donors. PBMCs were stimulated with pokeweed mitogen (PWM) to induce IgG1 production or Strept-Biotin IgG1/IgG2 to induce antibody triggered signaling. Before any stimulation, cells were pretreated with vehicle (0.01% DMSO) or AHR ligands TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin), ITE (2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), FICZ (6-formylindolo(3,2-b) carbazole), or I3C (indole 3 carbinol). Results: Our data revealed that PWM stimulation significantly increased IL6 and IL1B gene expression and PWM induced IL-6 cytokine secretion, which was significantly suppressed by TCDD, ITE, FICZ, and I3C. However, only TCDD was able to suppress PWM-stimulated IgG1 antibody production. Transcriptomic analysis revealed that I3C upregulated PWM induced canonical AHR signaling genes such as CYP1A1, CYP1B1, AHRR and TIPARP in human PBMC. Notably, I3C downregulated genes TRAPPC9 and C1QTNF3, which play a role in NF-κB-associated inflammatory signaling. It also revealed potential sex differences in I3C-mediated gene modulation associated with B cell function, Ig expression, FcγR signaling, and inflammatory pathways. Lastly, IgG1 and IgG2 immune complex stimulated IL-6 cytokine secretion was significantly suppressed by TCDD, whereas I3C showed modest suppression. Conclusions: These findings demonstrate that AHR activation suppressed antibody production and IgG-mediated immune signaling in human PBMCs.
