title: SHP-1 is directly activated by the aryl hydrocarbon receptor and regulates BCL-6 in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
abstract: The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a strong AHR agonist, causes significant suppression of human B cell activation and differentiation. The current studies describe the identification of Src homology phosphatase 1 (SHP-1) encoded by the gene PTPN6 as a putative regulator of TCDD-mediated suppression of B cell activation. Shp-1 was initially identified through a genome-wide analysis of AHR binding in mouse B cells in the presence of TCDD. The binding of AHR to the PTPN6 promoter was further confirmed using electrophoretic mobility shift assays in which, specific binding of AHR was detected at four putative DRE sites within PTPN6 promoter. Time-course measurements performed in human B cells highlighted a significant increase in SHP-1 mRNA and protein levels in the presence of TCDD. The changes in the protein levels of SHP-1 were also observed in a TCDD concentration-dependent manner. The increase in SHP-1 levels was also seen to occur due to a change in early signaling events in the presence of TCDD. We have shown that BCL-6 regulates B cell activation by repressing activation marker CD80 in the presence of TCDD. TCDD-treatment led to a significant increase in the double positive (SHP-1hiBCL-6hi) population. Interestingly, treatment of naïve human B cells with SHP-1 inhibitor decreased BCL-6 protein levels suggesting possible regulation of BCL-6 by SHP-1 for the first time. Collectively, these results suggest that SHP-1 is regulated by AHR in the presence of TCDD and may, in part through BCL-6, regulate TCDD-mediated suppression of human B cell activation.
authors.affiliation: Genetics Program, Michigan State University, East Lansing, MI 48824, United States; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Ashwini S
authors.initials: AS
authors.lastname: Phadnis-Moghe
authors.affiliation: Genetics Program, Michigan State University, East Lansing, MI 48824, United States; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Jinpeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.affiliation: Institute for Integrative Toxicology, Michigan State University, East Lansing, MI 48824, United States; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States. Electronic address: kamins11@msu.edu.
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*
chemical_list: C084103:BCL6 protein, human; D000072317:Polychlorinated Dibenzodioxins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
keywords: Aryl hydrocarbon receptor; Human B cell activation; PTPN6; SHP-1; TCDD immunotoxicity