title: Simultaneous in vivo time course and dose response evaluation for TCDD-induced impairment of the LPS-stimulated primary IgM response.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity but the specific molecular mechanisms responsible for immunosuppression by TCDD are poorly understood. In vivo and in vitro studies of the primary humoral IgM response demonstrated that the B cell is a sensitive cell type to modulation by TCDD. We hypothesized that in vivo administration of TCDD disrupts expression of transcription factors controlling B cell to plasma cell differentiation. Female C57BL6 mice were treated with a single dose of TCDD (3, 10, or 30 microg/kg) and/or vehicle (sesame oil). On day 4 post-TCDD administration mice were sensitized with 25 microg lipopolysacchride (LPS) by intraperitioneal injection to stimulate an immune response. Splenocytes were isolated on subsequent days following LPS, up to 3 days post-LPS, and the expression of IgM, XBP-1, PAX5, BCL-6, and Blimp-1 was assessed. TCDD treatment dose-dependently suppressed LPS-induced IgM antibody-forming cell number, which was correlated with decreased frequency of CD19+ CD138+ cells. Gene expression analysis revealed that TCDD caused a dose-dependent suppression of Igmicro chain, Igkappa chain, IgJ chain, XBP-1, and Blimp-1. TCDD also dose-dependently suppressed LPS-stimulated increases in Blimp-1 protein expression in CD19+ B cells. The deregulation of Blimp-1 expression by TCDD provides a partial explanation for the concomitant suppression of the IgM response and confirms previous observations established in vitro.
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Colin M
authors.initials: CM
authors.lastname: North
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.forename: Haitian
authors.initials: H
authors.lastname: Lu
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D007075:Immunoglobulin M / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D007075:Immunoglobulin M; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; C513258:Prdm1 protein, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D000074462:Positive Regulatory Domain I-Binding Factor 1
references.citation: Annu Rev Immunol. 2003;21:205-30
references.pmid: 12524387
references.citation: Mol Cell Biol. 2002 Jul;22(13):4771-80
references.pmid: 12052884
references.citation: Toxicol Sci. 2005 Jun;85(2):1048-63
references.pmid: 15800033
references.citation: J Immunol. 1988 Feb 1;140(3):928-35
references.pmid: 3257509
references.citation: J Biochem. 2007 Jun;141(6):783-9
references.pmid: 17569706
references.citation: Mol Pharmacol. 1998 Apr;53(4):623-9
references.pmid: 9547351
references.citation: J Immunol. 2005 Jun 15;174(12):7703-10
references.pmid: 15944271
references.citation: Int Immunopharmacol. 2002 Feb;2(2-3):277-91
references.pmid: 11811931
references.citation: Toxicol Appl Pharmacol. 1994 Feb;124(2):248-56
references.pmid: 8122270
references.citation: J Immunol. 2004 Jul 15;173(2):1158-65
references.pmid: 15240705
references.citation: Eur J Immunol. 2007 Oct;37(10):2923-36
references.pmid: 17724683
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Toxicol Environ Health A. 2006 Mar;69(5):367-80
references.pmid: 16455615
references.citation: Toxicol Sci. 2004 Feb;77(2):272-9
references.pmid: 14600275
references.citation: Immunity. 2006 Mar;24(3):283-93
references.pmid: 16546097
references.citation: J Pharmacol Exp Ther. 1984 May;229(2):493-500
references.pmid: 6716271
references.citation: Immunopharmacology. 1993 Sep-Oct;26(2):105-12
references.pmid: 8282534
references.citation: Fundam Appl Toxicol. 1996 Jan;29(1):40-7
references.pmid: 8838638
references.citation: Proc Soc Exp Biol Med. 1969 Nov;132(2):575-81
references.pmid: 5355110
references.citation: J Pharmacol Exp Ther. 2004 Apr;309(1):71-8
references.pmid: 14718603
references.citation: Science. 2008 Jun 13;320(5882):1492-6
references.pmid: 18556558
references.citation: Toxicology. 1991;69(3):219-55
references.pmid: 1949050
references.citation: Chem Biol Interact. 1980 Jun;30(3):337-42
references.pmid: 7379212
references.citation: Nature. 1996 Jun 27;381(6585):751-8
references.pmid: 8657279
references.citation: J Pharmacol Exp Ther. 2008 Aug;326(2):463-74
references.pmid: 18483191
references.citation: Immunopharmacology. 1983 Aug;6(2):143-53
references.pmid: 6309701
references.citation: Toxicology. 2004 Aug 5;200(2-3):235-46
references.pmid: 15212819
references.citation: Immunity. 2000 Aug;13(2):199-212
references.pmid: 10981963
references.citation: Dermatol Clin. 1990 Jan;8(1):209-13
references.pmid: 2406060
references.citation: Semin Immunol. 2008 Feb;20(1):49-58
references.pmid: 18222702
references.citation: J Toxicol Environ Health. 1990 Nov;31(3):203-15
references.pmid: 1700136
references.citation: Exp Mol Pathol. 2005 Feb;78(1):25-35
references.pmid: 15596057
references.citation: Fundam Appl Toxicol. 1996 Aug;32(2):293-7
references.pmid: 8921333
references.citation: Immunopharmacology. 1988 Nov-Dec;16(3):167-80
references.pmid: 3267010
references.citation: Immunity. 2003 Oct;19(4):607-20
references.pmid: 14563324
references.citation: J Exp Med. 2000 Jul 3;192(1):23-9
references.pmid: 10880523
references.citation: Nature. 2001 Jul 19;412(6844):300-7
references.pmid: 11460154
references.citation: Mol Pharmacol. 1986 Apr;29(4):372-7
references.pmid: 3486342
references.citation: J Exp Med. 2004 Oct 18;200(8):967-77
references.pmid: 15492122
references.citation: J Immunol. 1999 Apr 1;162(7):3749-52
references.pmid: 10201887
references.citation: Toxicol Sci. 2009 Apr;108(2):377-88
references.pmid: 19237549
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):14988-93
references.pmid: 17846422
references.citation: Toxicol Appl Pharmacol. 2001 Mar 15;171(3):157-64
references.pmid: 11243915