Assistant Professor of Research
Asthma and Allergic Diseases Center
Office (434) 982-3270
1)Molecular genetic studies in allergic disease and asthma:
Polymorphisms have been described in the interleukin (IL)-10 , IL-9 and leukotriene C4 synthase promoters that link in several population studies to the presence of allergies and asthma. The IL-10 promoter polymorphism is a C/A base exchange at ‑517 that is located between putative binding sites for two transcription factors. We have demonstrated that the upstream site is bound by a Sp1/Sp3 heterodimer and the downstream site is bound by a member of the ets transcription factor family. Using functional studies, we have shown that this single base change alters IL-10 promoter activity and that Sp1 acts as a transcriptional repressor. We are currently determining the role of this polymorphism on IL-10 promoter activity in purified lymphocyte populations and the influence of the polymorphism on response to immunotherapy.
2)Determine the molecular mechanism of nasal polyp formation:
Nasal polyposis is a disease characterized by the recurrent growth of tissue from the middle turbinant of the sinus tissue. The mechanism of polyp formation is unknown so we have begun studies to characterize cellular components that are involved in directing and maintaining polyp growth. We have found and overexpression of cysteinyl leukotrienes and the enzymes involved in their synthesis is polyp tissue compared to controls. Fibroblasts derived from polyp tissue were responsive to IL-4 and resulted in upregulation of cytokines and chemokines involved in fibrosis and inflammatory cell recruitment helping to create a feedback loop that results in persistent inflammation. We are currently investigating the role of lysophosphatidic acid in mediating epithelial cell damage.
3)Germinal center-specific gene transcription:
We are defining the significance of pax-5 and Sp1/Sp3 in the tissue specific expression of the germinal center-associated protein M17, a gene associated with small B cell lymphoma in humans. These studies extend beyond pre-B cells an important role for pax-5 in B-cell differentiation, synergistic activation of M17 transcription by Sp1 and Sp3 and interaction of pax-5 with the Sp1/Sp3 complex to mediate transcriptional activity.
Steinke, J.W., Kopytek, S.J., and Peterson, D.O. Discrete promoter elements affect specific properties of RNA polymerase II transcription complexes Nucleic Acids Research 28:2726-2735 (2000)
Routes, J.M., Ryan, S., Li, H., Steinke, J., and Cook, J.L. Dissimilar immunogenicities of human papillomavirus E7 and adenovirus E1A proteins influences primary tumor development Virology 277:48-57 (2000)
Steinke, J.W., Bradley, D., Arango, P., Crouse, D., Frierson, H., Kountakis, S.E., Kraft, M. and Borish, L. Cysteinyl leukotriene expression in chronic hyperplastic sinusitis/nasal polyposis Journal of Allergy and Clinical Immunology 111:342-349 (2003)
Steinke, J.W., Crouse, C.D., Bradley, D., Hise, K., Lynch, K., Kountakis, S.E., and Borish, L. Characterization of IL-4 stimulated nasal polyp fibroblasts American Journal of Respiratory Cell and Molecular Biology 30:212-219 (2004)
Steinke, J.W. Anti-IL4 therapy. Immunology and Allergy Clinics of North America (in press) (2004)