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2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity, disrupting antibody production in response to both T cell-dependent and T cell-independent antigens. Among the cell types required for humoral responses, the B cell is highly, and directly, sensitive to TCDD. B cells become antibody-secreting cells via plasmacytic differentiation, a process regulated by several transcription factors, including activator protein-1, B-cell CLL/lymphoma 6 (BCL-6), and B lymphocyte-induced maturation protein 1 (Blimp-1). The overarching conceptual framework guiding experimentation is that TCDD disrupts plasmacytic differentiation by altering the expression or activity for upstream regulators of Blimp-1. Multiparametric flow cytometry was used to investigate TCDD-induced alterations in both activation marker and transcription factor expression following lipopolysaccharide (LPS) activation of purified B cells. TCDD significantly impaired LPS-activated expression of major histocompatibility complex class II, cluster of differentiation (CD)69, CD80, and CD86. Immunosuppressive concentrations of TCDD also suppressed LPS-activated Blimp-1 and phosphorylated c-Jun expression, whereas elevating BCL-6 expression. Because BCL-6 and c-Jun are directly and indirectly regulated by the kinases AKT, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), it was hypothesized that TCDD alters toll-like receptor-activated kinase phosphorylation. TCDD at 0.03 and 0.3 nM significantly impaired phosphorylation of AKT, ERK, and JNK in CH12.LX B cells activated with LPS, CpG oligonucleotides, or resiquimod (R848). In primary B cells, R848-activated phosphorylation of AKT, ERK, and JNK was also impaired by TCDD at 30 nM. These results suggest that impairment of plasmacytic differentiation by TCDD involves altered transcription factor expression, in part, by suppressed kinase phosphorylation.

toxicological sciences

2,3,7,8-Tetrachlorodibenzo-p-dioxin–Mediated Suppression of Toll-Like Receptor Stimulated B-Lymphocyte Activation and Initiation of Plasmacytic Differentiation