Suppression of the IgM Response by Aryl Hydrocarbon Receptor Activation in Human Primary B Cells Involves Impairment of Immunoglobulin Secretory Processes

AbstractAryl hydrocarbon receptor (AHR) activation by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is well established at suppressing humoral immunity. Previous studies in mouse B cells revealed that decreased IgM production was due to a significant suppression in the mRNA levels of the immunoglobulin M components (IgH, IgJ, and Igκ chains) and subsequent decrease in IgM synthesis. In contrast, the current study shows that activation of AHR in human B cells also results in a significant suppression of the number of IgM-secreting cells, but this is not due to a decrease in the transcription or translation of IgH, IgJ, and Igκ chains. Instead, the reduced humoral response is due to the impairment of IgM secretion. This is further evidenced by an accumulation of intracellular IgM in human B cells, which indicates that activation of AHR alters distinct regulatory pathways in human and mouse B cells leading to the suppressed primary IgM response. Collectively, these results demonstrate that although AHR activation mediates suppression of humoral immune responses across many different animal species, the mechanism of action is not necessarily conserved across species.

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Induction of the Aryl Hydrocarbon Receptor–Responsive Genes and Modulation of the Immunoglobulin M Response by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary Human B Cells

Toxicological Sciences ◽

10.1093/toxsci/kfq234 ◽

2010 ◽

Vol 118 (1) ◽

pp. 86-97 ◽

Cited By ~ 21

Author(s):

Haitian Lu ◽

Robert B. Crawford ◽

Jose E. Suarez-Martinez ◽

Barbara L. F. Kaplan ◽

Norbert E. Kaminski

Keyword(s):

B Cells ◽

Aryl Hydrocarbon Receptor ◽

Immunoglobulin M ◽

Aryl Hydrocarbon ◽

Human B Cells ◽

Tetrachlorodibenzo P Dioxin

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Identification of a Sensitive Human Immunological Target of Aryl Hydrocarbon Receptor Activation: CD5+ Innate-Like B Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.635748 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lance K. Blevins ◽

Jiajun Zhou ◽

Robert B. Crawford ◽

Norbert E. Kaminski

Keyword(s):

B Cells ◽

B Cell ◽

Aryl Hydrocarbon Receptor ◽

Immune Cell ◽

Broad Class ◽

Cd40 Ligand ◽

Receptor Activation ◽

Immunoglobulin M ◽

Cell Repertoire ◽

Aryl Hydrocarbon

Xenobiotic-mediated activation of the aryl hydrocarbon receptor (AHR) is immunotoxic in a number of immune cell types, with the B cell being a well-established sensitive target. Recent advances have provided evidence that the B cell repertoire is a heterogeneous population, with subpopulations exhibiting vastly different cellular and functional phenotypes. Recent work from our laboratory identified the T cell specific kinase lck as being differentially regulated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent activator of AHR. While LCK is primarily expressed in T cells, a subset of CD5+ B cells also express LCK. CD5 positivity describes a broad class of B lymphocytes termed innate-like B cells (ILBs) that are critical mediators of innate immunity through constitutive secretion of polyvalent natural immunoglobulin M (IgM). We hypothesized that CD5+ ILBs may be sensitive to AHR-mediated immunotoxicity. Indeed, when CD5+ B cells were isolated from the CD19+ pool and treated with TCDD, they showed increased suppression of the CD40 ligand-induced IgM response compared to CD5- B cells. Further, characterization of the CD5+ population indicated increased basal expression of AHR, AHR repressor (AHRR), and cytochrome p450 family 1 member a1 (CYP1A1). Indeed the levels of AHR-mediated suppression of the IgM response from individual donors strongly correlated with the percentage of the B cell pool that was CD5+, suggesting that CD5+ B cells are more sensitive to AHR-mediated impairment. Together these data highlight the sensitive nature of CD5+ ILBs to AHR activation and provide insight into mechanisms associated with AHR activation in human B cells.

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Lymphocyte-Specific Protein Tyrosine Kinase (LCK) is Involved in the Aryl Hydrocarbon Receptor-Mediated Impairment of Immunoglobulin Secretion in Human Primary B Cells

Toxicological Sciences ◽

10.1093/toxsci/kfy133 ◽

2018 ◽

Vol 165 (2) ◽

pp. 322-334

Author(s):

Jiajun Zhou ◽

Qiang Zhang ◽

Joseph E Henriquez ◽

Robert B Crawford ◽

Norbert E Kaminski

Keyword(s):

B Cells ◽

Tyrosine Kinase ◽

Aryl Hydrocarbon Receptor ◽

Protein Tyrosine Kinase ◽

Specific Protein ◽

Immunoglobulin M ◽

Protein Tyrosine ◽

Immunoglobulin Secretion ◽

Aryl Hydrocarbon

AbstractThe aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation, and cell development. In humans, the activation of AHR by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR-activated human primary B cells. LCK is a well-characterized tyrosine kinase that phosphorylates critical signaling proteins involved in activation and cytokine production in T cells. Conversely, the role of LCK in human primary B cells is not well understood. In the current studies, we have verified the transcriptomic finding by detecting AHR-mediated upregulation of LCK protein in human primary B cells. We also confirmed the role of AHR in the upregulation of LCK by using a specific AHR antagonist, which abolished the AHR-mediated increase of LCK. Furthermore, we have confirmed the role of LCK in the AHR-mediated suppression of IgM by using LCK specific inhibitors, which restored the IgM secretion by human B cells in the presence of TCDD. Collectively, the current studies demonstrate a novel role of LCK in IgM response and provide new insights into the mechanism for AHR-mediated impairment of immunoglobulin secretion by human primary B cells.

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Aryl Hydrocarbon Receptor Activation by TCDD Modulates Expression of Extracellular Matrix Remodeling Genes during Experimental Liver Fibrosis

BioMed Research International ◽

10.1155/2016/5309328 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Cheri L. Lamb ◽

Giovan N. Cholico ◽

Daniel E. Perkins ◽

Michael T. Fewkes ◽

Julia Thom Oxford ◽

...

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Liver Injury ◽

Aryl Hydrocarbon Receptor ◽

Receptor Activation ◽

Matrix Remodeling ◽

Mrna Levels ◽

Gelatinase Activity ◽

Ecm Remodeling ◽

Aryl Hydrocarbon

The aryl hydrocarbon receptor (AhR) is a soluble, ligand-activated transcription factor that mediates the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Increasing evidence implicates the AhR in regulating extracellular matrix (ECM) homeostasis. We recently reported that TCDD increased necroinflammation and myofibroblast activation during liver injury elicited by carbon tetrachloride (CCl4). However, TCDD did not increase collagen deposition or exacerbate fibrosis in CCl4-treated mice, which raises the possibility that TCDD may enhance ECM turnover. The goal of this study was to determine how TCDD impacts ECM remodeling gene expression in the liver. Male C57BL/6 mice were treated for 8 weeks with 0.5 mL/kg CCl4, and TCDD (20 μg/kg) was administered during the last two weeks. Results indicate that TCDD increased mRNA levels of procollagen types I, III, IV, and VI and the collagen processing molecules HSP47 and lysyl oxidase. TCDD also increased gelatinase activity and mRNA levels of matrix metalloproteinase- (MMP-) 3, MMP-8, MMP-9, and MMP-13. Furthermore, TCDD modulated expression of genes in the plasminogen activator/plasmin system, which regulates MMP activation, and it also increased TIMP1 gene expression. These findings support the notion that AhR activation by TCDD dysregulates ECM remodeling gene expression and may facilitate ECM metabolism despite increased liver injury.

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