Courtney E.W. Sulentic, Ph.D.
Campus Address: 206 Health Sciences Building
Office Phone: 937-775-3583
Fax: (937) 775-7221
B.S. (1992), Lake Superior State University, Sault Ste. Marie, Mich.
Ph.D. (1999), Michigan State University, Lansing, Mich.
Postdoctoral (1999-2003), Michigan State University, Lansing, Mich.
- Toxicology — immunological and nanoparticles
- Mechanisms of immune modulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and other chemicals with particular emphasis on immunoglobulin heavy chain gene regulation
The research focus of my laboratory is in the area of immunotoxicology and involves understanding, at the molecular level, the impact on B cell function of various chemicals from environmental, industrial, dietary and pharmaceutical origin. B cells are an important effector cell in maintaining immunity against a wide variety of pathogens. B cells produce and secrete antibodies which have the ability to recognize specific antigens (i.e., foreign molecules) and lead to the clearance of these antigens from the body. B cells and antibodies therefore play an important role in host protection. Exposure to exogenous chemicals either through the diet, pharmaceuticals or environment may impair immune function. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin or dioxin) has been identified as a potent suppressor of B cell function by markedly inhibiting antibody secretion. This is of human relevance and toxicological interest since TCDD is only one representative of a large class of environmental chemicals. The toxic effects of these chemicals may be mediated through the aryl hydrocarbon receptor (AhR) signaling pathway.
The AhR is a cytosolic protein which has affinity for TCDD and like compounds. Binding of TCDD to the AhR results in nuclear translocation of the ligand-receptor complex where it forms a heterodimer with the AhR nuclear translocator (ARNT). The AhR-ARNT complex is a transcription factor that binds to the DNA at dioxin responsive elements within regulatory regions of sensitive genes and regulates transcription. In addition to directly activating the AhR signaling pathway, TCDD has also been shown to modulate the activity of other signaling pathways including the NF-κB/Rel pathway. The specific interactions between the AhR and NF-κB/Rel pathways are unclear and may be important in the effects of TCDD on B cell function, specifically the inhibition of immunoglobulin (Ig) expression and antibody secretion (secreted form of Ig). We have found that a regulatory region 3' of the Ig heavy chain gene (IgH) is a sensitive target of TCDD and that inhibition of this region may involve both the AhR and NF-κB/Rel proteins. The 3'IgH RR has been purported to regulate IgH expression and isotype class switching. Our research goal is to understand the molecular interactions between the AhR and NF-κB/Rel proteins at the 3'IgH regulatory region in order to elucidate their role in TCDD-induced inhibition of IgH expression.
The 3'IgH RR has been associated with the occurrence and severity of specific human autoimmune diseases. Chemical-induced alteration in the regulation of the 3'IgH RR may be significant in discovering the presently elusive etiology of some autoimmune diseases. Clearly, understanding how chemicals modify the 3'IgH RR and IgH expression will lead to a better understanding of the basic physiology of IgH expression and will ultimately lead to improved drug development and prediction of potential toxic interactions.
We utilize several molecular and cellular biology techniques including cell culture of cell lines and primary cells, Western blotting, EMSA analysis, in vitro DNA transfection of mammalian cells, ELISA analysis, and flow cytometry.
Wourms, M. J. and Sulentic, C. E. W.: The aryl hydrocarbon receptor regulates an essential transcriptional element in the immunoglobulin heavy chain gene. Cellular Immunology, in revision
Sharma, M., Salisbury, R., Hussain, S., Sulentic, C. E. W.: Gold nanoparticles induce transcriptional activity of NF-κB in a B-lymphocyte cell line. Nanoscale, 5:3747 (2013).
Barchowsky, A., Buckley, L. A., Carlson, G. P., Fitsanakis, V. A., Ford, S. M., Genter, M., Germolec, D. R., Leavens, T. L., Lehman-McKeeman, L. D., Safe, S. H., Sulentic, C. E. W., Eidemiller, B. J.: The Toxicology Education Summit: building the future of toxicology through education, Toxicological Sciences, 127:331-338 (2012).
Ochs, S., Liu, J., Fernando, T., Fecher, R., Sulentic, C. E. W.: A dioxin response element in the multiple cloning site of the pGL3 luciferase reporter influences transcriptional activity, Toxicology in Vitro, 26:979-984 (2012).
Fernando, T., Ochs, S., Liu, J., Chambers-Turner, R., Sulentic, C. E. W.: 2,3,7,8-Tetracholorodibenzo-p-dioxin Induces Transcriptional Activity of the Human Polymorphic hs1,2 Enhancer of the 3’Igh Regulatory Region, Journal of Immunology, 188:3294-3306 (2012).
Romer, E.J., Sulentic, C.E.W.: Hydrogen peroxide modulates immunoglobulin expression by targeting the 3’Igh regulatory region through an NFκB-dependent mechanism. Free Radical Research, 45:796-809 (2011).
Henseler, R.A., Romer, E.J., Sulentic, C.E.W.: Chemical-induced Modulation of the 3'IgH regulatory region in the CH12.LX Cell Line: an in vitro Model for Identifying Immunotoxicants that Target B Cell Function. Toxicology, 261:9-18 (2009).
Xiang Z., Schweitzer, B.L., Romer, E.J., Sulentic, C. E. W., DeKoter, R.P.: Ectopic Expression of Spi-C Impairs B Cell Development and Function. European Journal of Immunology, 38:2587-2599 (2008).
Sulentic, C.E.W., Wei, Z., Na, Y.J., Kaminski, N.E.: 2,3,7,8-Tetrachlorodibenzo-p-dioxin, an Exogenous Modulator of the 3'α Immunoglobulin Heavy Chain Enhancer in the CH12.LX Mouse Cell Line. J. Pharm. Exp. Ther. 309:71-78 (2004).
Sulentic, C. E. W., Kang, J.S., Na, Y.J., Kaminski, N.E.: Regulation of the 3'α-hs4 Domain by DRE and κB Binding Proteins. Toxicology. 200:235-246 (2004).
Crawford, R. B., Sulentic, C. E. W., Yoo, B.S., Kaminski, N.E.: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the regulation and posttranslational modification of p27kip1 in lipopolysaccharide-activated B cells. Toxicol. Sciences, 75:333-342 (2003).
Kaminski, N. E., Sulentic, C.E.W., Kang, J.S.: Looking inside the cell for mechanisms of Immunotoxicity: Experimental Design & Approaches Aimed Toward Elucidation of TCDD-mediated B cell Dysfunction. J. Toxicol. Public Health 17:205-210 (2000).
Sulentic, C.E.W., Holsapple, M.P., Kaminski, N.E.: 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. Pharm. Exp. Ther., 295:705-716 (2000). [Abstract]
Sulentic, C.E.W., Holsapple, M.P., Kaminski, N.E.: AhR-dependent Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin of IgM Secretion in Activated B cells. Mol. Pharm., 53:623-629 (1998).
Williams, C.E., Crawford, R.B., Holsapple, M.P., Kaminski, N.E.: Identification of Functional Aryl Hydrocarbon Receptor and Aryl Hydrocarbon Receptor Nuclear Translocator in Murine Splenocytes. Biochem. Pharmacol. 52:771-780 (1996). [Abstract]
Peer-reviewed Review Publications
Sulentic, C. E. W. and Kaminski, N. E.: The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Toxicological Sciences, 120:S171-S191 (2011). Solicited for the 50th Anniversary of the Society of Toxicology.
Kaplan, B. L. F., Sulentic, C. E. W., Holsapple, M. P., Kaminski, N. E.: Chapter 12: Toxic Responses of the Immune System. In: Casarett & Doull’s Toxicology, The Basic Science of Poisons (ed. C. D. Klaassen) 8th edition, McGraw-Hill, USA (2013).
Solicited, Nonpeer-reviewed Publications
Sulentic, C.E.W.: Modulation of Immunoglobulin Gene Expression. In: Current Protocols in Toxicology Unit 18.13, John Wiley & Sons, Inc., Hoboken, N.J. (2008).
Sulentic, C.E.W. and Kaminski, N.E.: Humoral Immunity. In: Encyclopedic Reference of Immunotoxicology (ed. H.-W. Vohr) XXII, 730, Springer Press Heidelberg, Germany (2005).
Kaminski, N.E. and Sulentic, C.E.W.: B cell. In: Encyclopedic Reference of Immunotoxicology (ed. H.-W. Vohr) XXII, 730, Springer Press Heidelberg, Germany (2005).
Publications in Review or Preparation
Grabinski, C., Sharma, M., Maurer, E., Sulentic, C. E. W., Sankaran, M., Hussain, S.: The effect of shear flow on nanoparticle agglomeration and deposition in in vitro dynamic flow models. In review
Salisbury, R., Sulentic, C. E. W.: Role of the AhR and NF-κB/Rel proteins in 3’Igh RR inhibition by TCDD.
Ochs, S., Snyder, A., Johnson, B., Sulentic, C. E. W.: TCDD-induced activation of the human IgH hs1,2 enhancer is dependent on the AhR and the NF-1 transcription factor binding site within the polymorphic region.