Indole-3-Carbinol (I3C) suppression of IgG2b-triggered signaling in innate cells involves early suppression of p-Akt.

Immunoglobulin G (IgG) plays a crucial role in immune defence mechanisms, yet IgG antibodies can contribute to the pathology of autoimmune diseases like multiple sclerosis (MS). Our prior work demonstrated that the aryl hydrocarbon receptor (AHR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed antibody production in the animal model of MS. However, relatively little is known about other downstream cellular effects of compromised antibody production. In this study, we investigated how AHR ligand suppression of IgG antibodies has the potential to impact Fcγ receptor (FcγR) signaling in innate immune cells. Our findings revealed that although TCDD suppressed IgG1, IgG2a, and IgG2b antibody production in vivo, streptavidin (Strept)-biotinylated IgG1 (Biotin IgG1) immune complex-triggered innate cell activation was modestly affected by several AHR ligands in vitro in mouse splenocytes (SPLC) and RAW 264.7 macrophages. To address the role of other IgG isotypes, we noted that IgG2a complexes failed to stimulate SPLC or RAW 264.7 cells, but it stimulated BV2 microglia cells. In contrast, IgG2b robustly activated SPLC, RAW 264.7, and BV2 cells. IgG2b-triggered IL-6 and TNF-α cytokine secretion was significantly suppressed by the dietary AHR ligand indole-3-carbinol (I3C) in both female splenocytes (SPLC) and RAW 264.7 cells. To further understand the underlying molecular mechanism behind the cellular effect of I3C, we analyzed Akt signaling, which is commonly activated in response to FcγR activation. We found that Strept-Biotin IgG2b stimulation increased phosphorylation of Akt, and I3C transiently inhibited IgG2b-induced Akt phosphorylation. Collectively, these findings show that I3C could be a potential nontoxic anti-inflammatory therapeutic strategy through inhibition of antibody-triggered signaling and Akt activation, which could be beneficial in MS.