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Research Interests
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 small secreted proteins called cytokines. Interleukin-4
(IL-4) is a cytokine produced by T cells, mast cells, 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. Three major signal transduction pathways
have been found to be 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.
Selected Publications Top
Wang, H.Y., Zamorano, J. and Keegan, A.D. 1998. A role for the I4R-motif
of
the IL-4Ra in regulating activation of the IRS2 and STAT6 pathways: Analysis
by mutagenesis. J. Biol. Chem. 273:9898-9905.
Wang, H. Y., Shelburne, C. P., Zamorano, J., Kelly, A. E., Ryan, J. J.,
and
Keegan, A. D. 1999. Effects of an allergy-associated mutation in the
huIL-4Ra (Q576R) on huIL-4-induced signal transduction. J. Immunol. 162:
4385-4389.
Li, L., Wickham, T.J., and Keegan, A. D. 2001. Efficient transduction
of
murine B lymphocytes and B lymphoma lines by modified adenoviral vectors.
Gene Therapy. 8: 938-945.
Zamorano, J., Mora, A., Boothby, M.R., and Keegan, A.D. 2001. NFkB
activation plays an important role in the IL-4-induced protection from
apoptosis.. Intl. Immunol. 13: 1479-87.
Perez, G., Melo, M., Keegan, A.D., and Zamorano, J. 2002. Aspirin and
salicylates inhibit the IL-4 and IL-13-induced activation of STAT6. J.
Immunol. 168: 1428-34.
Contact Information Top
Dr. Achsah D. Keegan
Senior Scientist
Immunology Department, Holland Laboratory
American Red Cross
15601 Crabbs Branch Way
Rockville, MD 20855
301 517-0326
keegana@usa.redcross.org
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