Progress 01/01/00 to 12/31/04
Outputs
Inhibition of immunoglobulin secretion by TCDD is one of the most sensitive toxic sequelae produced by TCDD exposure. The results from the first 4 years of this project provide the first definitive linkage between TCDD-mediated immunoglobulin secretion and an intracellular target that is directly involved with immunoglobulin regulation. Results from Year 4 of this project have provided important new information in two specific areas concerning the molecular mechanism by which TCDD alters B cell function. First, we have successfully demonstrated that TCDD treatment of LPS activated B cells results in direct effects on the transcriptional activity mediated through the 3'alpha enhancer associated with the gene that codes for the immunoglobulin heavy chain. We believe this is a critical observation toward developing an understanding of the mechanism by which TCDD inhibits immunoglobulin secretion by B cells. Second, our results provide new and important insight into the
molecular mechanism by which TCDD alters the differentiation of B cells into antibody secreting plasma cells. Our results show that TCDD significantly alters the regulation of a critical regulator of the cell cycle, p27, through changes in phosphorylation and protein in LPS activated B cells.
Impacts
The potential health risks to man associated with the release of TCDD into the environment is a major concern. The immune system is one of the most sensitive organ systems targeted by TCDD with the B cell being the most sensitive cell type to TCDD-mediated alterations within the immune system. The present studies are directed toward elucidating the cellular molecular mechanism by which TCDD inhibits B cell function, which in turn results in a decrease in immune competence.
Publications
- Suh, J., Kang, J.S., Yang, K.H. and Kaminski, N.E. 2001. Antagonism by di-ortho polychlorinated biphenyls of aryl hydrocarbon receptor-dependent modulation of CYP1a1 and LPS-induced IgM gene expression in CH12.LX B cells. Organohalogen Compounds 53:342-345.
- Suh, J., Jeon, Y.J., Kim, H.M., Kang, J.S., Kaminski, N.E. and Yang, K.H. 2002. Aryl hydroarbon receptor-dependent inhibition of AP-1 activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in activated B cells. Toxicol. Appl. Pharmacol. 181:116-123.
- Sulentic, C.E., Na, Y.J., Oestreich, J.H., Holsapple, M.P. and Kaminski, N.E. 2002. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin inhibits transcriptional activity of the 3'alpha enhancer in lipopolysaccharide-stimulated CH12.LX B-cells. The Toxicologist 66(1-S):836. (Abstract)
- Crawford, R.B., Liu, J., Holsapple, M.P. and Kaminski, N.E. 2002. 2,3,7,8-Tetrachlorodibenzo-p-dioxin alters the expression pattern of p27(kip1) in lipopolysaccharide-activated B-cells. The Toxicologist 66(1-S). (Abstract)
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Progress 01/01/01 to 12/31/01
Outputs
Inhibition of immunoglobulin secretion by TCDD is one of the most sensitive toxic sequelae produced by TCDD exposure. The results from the first 3 years of this project provide the first definitive linkage between TCDD-mediated immunoglobulin secretion and an intracellular target that is directly involved with immunoglobulin regulation. Results from Year 3 of this project have provided important new information in two specific areas concerning the molecular mechanism by which TCDD alters B cell function. First, we have successfully demonstrated that TCDD treatment of LPS activated B cells results in direct effects on the transcriptional activity mediated through the 3'alpha enhancer associated with the gene that codes for the immunoglobulin heavy chain. We believe this is a critical observation toward developing an understanding of the mechanism by which TCDD inhibits immunoglobulin secretion by B cells. Second, our results provide new and important insight into the
molecular mechanism by which TCDD alters the differentiation of B cells into antibody secreting plasma cells. Our results show that TCDD significantly alters the regulation of p27, a critical regulator of the cell cycle, in LPS activated B cells.
Impacts
The potential health risks to man associated with the release of TCDD into the environment is a major concern. The immune system is one of the most sensitive organ systems targeted by TCDD with the B cell being the most sensitive cell type to TCDD-mediated alterations within the immune system. The present studies are directed toward elucidating the cellular molecular mechanism by which TCDD inhibits B cell function, which in turn results in a decrease in immune competence.
Publications
- Sulentic, C.E., Kang, J., Holsapple, M.P. and Kaminski, N.E. 2001. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces transcriptional activity of the 3'alpha-HS4 enhancer. The Toxicologist 60(1):A123. (Abstract)
- Kaminski, N.E. 2001. Putative intracellular targets for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated inhibition of immunoglobulin secretion by B-cells. The Toxicologist 60(1):A955. (Abstract)
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Progress 01/01/00 to 12/31/00
Outputs
Inhibition of immunoglobulin secretion by TCDD is one of the most sensitive toxic sequelae produced by TCDD exposure. Although this immunotoxic response has been described by more than half a dozen laboratories during the past 25 years, little progress has been made toward elucidation of the cellular mechanism responsible for this phenomenon. We believe that the results from the first two years of this project provide the first definitive linkage between TCDD-mediated immunoglobulin secretion and an intracellular target that is directly involved with immunoglobulin regulation. Specifically, our results: 1) demonstrate that the AhR is requisite for TCDD-mediated inhibition of IgM secretion; 2) show that the inhibition of IgM secretion by TCDD is mediated, at least in part, through a decrease in the transcription of the IgM heavy chain; 3) identify DRE-like sites within the regulatory domains of the IgM heavy chain gene; 4) demonstrate that the AhR/ARNT bind to the
aforementioned DRE-like sites in the hs1, 2 and hs4 regulatory domains; and 5) through reporter gene assays we show that TCDD treatment modulates the transcriptional activity through at least the hs4 regulatory domain of the 3'alpha enhancer. We believe that these are perhaps the most significant studies to date in terms of providing a cellular molecular mechanism for the ability of TCDD to inhibit IgM secretion by B cells.
Impacts
The potential health risks to man associated with the release of TCDD into the environment is a major concern. The immune system is one of the most sensitive organ systems targeted by TCDD with the B cell being the most sensitive cell type to TCDD-mediated alterations within the immune system. The present studies are directed toward elucidating the cellular molecular mechanism by which TCDD inhibits B cell function, which in turn results in a decrease in immune competence.
Publications
- Sulentic, C.E., Holsapple, M.P. and Kaminski, N.E., 2000. A putative link between transcriptional regulation of IgM expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the aryl hydrocarbon receptor/dioxin-responsive enhancer signaling pathway. J. Pharmacol. Exp. Ther. 295(2):705-716.
- Sulentic, C.E.W., Kaminski, N.E. and Holsapple, M.P., 2000. The AhR signaling pathway and transcriptional regulation of IgM expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. The Toxicologist, Toxicol. Sci. 54(1):A1308. (Abstract)
- Stoughton, S.B.K., 2000. TCDD induced NF-KB binding to the KB consensus motif in murine B-cell lines. The Toxicologist, Toxicol. Sci. 54(1):A1306. (Abstract)
- Kang, J., Yang, K. and Kaminski, N.E., 2000. Modulation of mouse IgH 3'alpha-enhancer activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin and LPS. The Toxicologist, Toxicol. Sci. 54(1):A1309. (Abstract)
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