Dr. Keegan is a tenured Professor in the Department of Microbiology and Immunology, a member of the Center for Vascular and Inflammatory Diseases (CVID), and is Associate Director of the Medical Scientist Training Program at the University of Maryland School of Medicine. Dr. Keegan received a B.S. (major-Zoology) magna cum laude at Duke University in 1983 and was elected to Phi Beta Kappa. She received her Ph.D. in immunology from the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine in 1989, where she studied the regulation of CD23 and IgE production by IL-4 and LPS. She spent 3 years as a National Research Council fellow at the National Institutes of Health followed by another 2 years as Staff Fellow where she worked on the characterization of the IL-4 receptor and IL-4-induced signal transduction. In 1994, she joined the Immunology Department at the Holland Laboratory of the American Red Cross as a Staff Scientist (Assistant Professor equivalent), and remained there until 2004. During this time, Dr. Keegan was also on the faculty of the George Washington University Medical Center in Washington, DC, where she served as the Director of the Graduate Program in Immunology from 2001-2004. Dr. Keegan joined the faculty at the UMSOM in 2004. Dr. Keegan is a member of the American Association of Immunologists, American Society for Biochemistry and Molecular Biology, International Cytokine Society, International Society of Interferon and Cytokine Research, and the Society for Leukocyte Biology.
Cytokine Receptor Signaling, Apoptosis, Allergy, and Asthma, and myeloid cell function
Lymphocyte activation and clonal expansion forms the basis of a productive immune response to an antigenic challenge and often involves the collaboration between B and T cells. These processes are highly regulated by several factors, including cytokines. Interleukin-4 (IL-4) is a cytokine produced by T cells, mast cells, eosinophils, and basophils that has profound effects on immune regulation. These effects include the ability to regulate IgE production and the ability to act as a viability factor and a growth co-factor for B cells, T cells, and mast cells. IL-4 also regulates the lymphokine- producing phenotype of CD4+ helper T cells and the type of immune response elicited by a given pathogen (i.e. cell-mediated or antibody). This immune regulation can determine the type of immune response elicited by an antigenic challenge such as a transplanted tissue.
The major goal of our lab is to gain an understanding of the molecular mechanism by which IL-4 mediates these effects with the future goal of developing rational strategies for manipulating immune responses. Our recent efforts have focused on understanding the structure of the receptor for IL-4 and the signal transduction pathways activated in cells by the binding of IL-4 to its receptor. We analyze three major signal transduction pathways activated by the IL-4 receptor through the tyrosine kinases JAK1 and JAK3 including the Shc, STAT-6, and IRS pathways. We are focusing on understanding how these signaling pathways lead to the regulation of gene expression, cell proliferation, and the suppression of caspase activation leading to the protection from apoptosis. An additional major focus is to understand how these pathways contribute to the pathogenesis of allergic asthma in a mouse model. Furthermore, we are studying the mechanism by which IL-4 regulates the development and function of myeloid cells, including macrophages and osteoclasts.
Kelly-Welch, A.E., Melo, M.E.F., Ford, A., Noben-Trauth, N., Smith, E., Haudenschild, C., and Keegan, A.D. 2004. Complex Role of the IL-4Ra in a murine model of airway inflammation: Expression of the IL-4Ra on a non-lymphocytic cell of hematopoietic origin contributes to severity of inflammation. J. Immunol. 172: 4545-55.
Moreno, J.L., Mikailenko, I., Tondravi, M., and Keegan, A.D. 2007. IL-4 promotes the formation of functional multi-nucleated giant cells from macrophage precursors by a STAT6-dependent mechanism. J. Leuk. Biol. 82:
Carey, G.B., Semenova, E., Qi, X., and Keegan, A.D. 2007. IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and
apoptosis: Contribution of the PI-3¹kinase/Akt pathway. Cell Res. 17: 942-955.
Heller, N.M., Qi, X., Juntilla, I., Shirey, K.A., Vogel, S.N., Paul, W.E., and Keegan, A.D. 2008. Type I IL-4 Receptors Selectively Activate IRS-2 to Induce Target Gene Expression in Macrophages. Science Signaling. 1: 51, ra17. (See Summary, Abstract or Full Text)
Ford, A.Q., Heller, N.M., Stephenson, L., Boothby, M.R., and Keegan, A.D. 2009. An atopy-associated polymorphism in the ectodomain of the IL-4R¿ chain (V50) regulates the persistence of STAT6 phosphorylation. J. Immunol. 183: 1607-1616. PMCID: 2751580 NIHMSID: 144498.
Yu, M., Moreno, J.L., Stains, J.P., and Keegan, A.D. 2009. Complex Regulation of Tartrate-Resistant Acid Phosphatase (TRAP) Expression by IL-4: IL-4 Indirectly Suppresses RANKL- Mediated TRAP Expression But Modestly Induces its Expression Directly. J. Biol. Chem. 284: 32968-32979. PM; 2781712
Chapoval, S., Dasgupta, P., Dorsey, N.J., and Keegan, A.D. 2010. Regulation of the T helper cell Type 2 (Th2)/ T regulatory cell (Treg) balance by IL-4 and STAT6. J. Leuk. Biol. 87: 1011-1018. PMC 2872539
Chapoval, S.P., Dasgupta, P., Smith, E.P., DeTolla, L.J., Lipsky, M.M., Kelly-Welch, A.E., and Keegan, A.D. 2011. STAT6 expression in multiple cell types mediates the cooperative development of allergic airway disease. J. Immunol. 186:2571-83.
Yu, M., Moreno, J.L., and Keegan, A.D. 2011. NF-kB signaling participates in both Receptor Activator of NF-kB Ligand (RANKL) and interleukin-4 (IL-4) induced macrophage fusion. J. Immunol. 187(4):1797-806
Dasgupta, P., Chapoval, S.P., Smith, E.P., and Keegan, A.D. 2011. Transfer of in vivo primed transgenic T cells supports allergic lung inflammation and FIZZ1 and Ym1 production in an IL-4Rα and STAT6 dependent manner. BMC-Immunol. 12: 60.
Ford, A.Q., Dasgupta, P., Mikhailenko, I., Smith, E.P., Noben-Trauth, N., and Keegan, A.D. 2012. Adoptive transfer of IL-4R¿+ macrophages is sufficient to support Th2-driven alternative macrophage activation and to enhance eosinophilic inflammation in a mouse model of allergic lung inflammation. BMC-Immunol. Jan. 31 13(1): 6.
Dasgupta, P., and Keegan, A.D. 2012. Contribution of alternatively-activated macrophages to allergic lung inflammation: A tale of mice and men. J. Inn. Imm. In press.
Heller, N.M., Dasgupta, P. Dorsey, N.J., Chapoval, S.P., and Keegan, A.D. 2012. Chapter 3: The Type I and Type II receptor complexes for IL-4 and IL-13 differentially regulate allergic lung inflammation. Allergic Diseases. Highlights in the clinic, mechanisms and treatments. Celso Pereira, Ed. (ISBN: 978-953-51-0227-4), InTech, Rijeca, Croatia. Pages 43-82. NIHMS 405572
Luzina, I.G., Keegan, A.D., Heller, N.M., Rook, G.A.W., Shea-Donohue, T., and Atamas, S.P. 2012. Regulation of inflammation by interleukin-4: A review of “alternatives.” J. Leuk. Biol. 92: 753-764.
Nkyimbeng-Takwi, E.H., Shanks, K., Smith, E., Iyer, A., Lipsky, M., DeTolla, L., Kikutani, H., Keegan, A.D. and Chapoval, S.P. 2012. A critical functional role for neuroimmune semaphorin 4A in the experimental asthma severity. Mucosal Immunology. 5(4): 409-19.
Porter, H.A., Carey, G.C., and Keegan, A.D. 2012. Insulin receptor substrate (IRS) 1 expression enhances the sensitivity of 32D cells to chemotherapy-induced cell death. Exp. Cell Research. 318(14):1745-58. NIHMSID: 387346.
Heller, N.M., Gwinn, W.M., Constant, S.L., and Keegan, A.D. 2012. IL-4 engagement of the type I IL-4 receptor complex enhances murine eosinophil migration to eotaxin-1 in vitro. PLoS ONE. 7(6):e39673.
Heller, N.M, Qi, X., Gesbert, F., and Keegan, A.D. 2012. The extracellular and transmembrane domains of the gc and IL-13Ra1 chains, not their cytoplasmic domains, dictate the nature of signaling responses to IL-4 and IL-13. J. Biol. Chem. 287(38): 31948-61.
Atamas, S.P., Chapoval, S.P., and Keegan, A.D. 2013. Cytokines in Chronic Respiratory Diseases. F1000 Report. 5: 3. doi: 10.3410/B5-3
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