IL-10 is a multifunctional cytokine that regulates complex immune responses. Its normal function is to protect the host from uncontrolled inflammatory responses. However, IL-10 has also been implicated as an autocrine growth factor in several B-cell malignancies and stimulates B-cell mediated autoimmune disease. The normal and pathological functions of IL-10 are initiated by IL-10 receptor engagement and assembly into a signaling competent IL-10/IL-10R1/IL-10R2 complex. In addition to cellular IL-10 (clL-10), Epstein Barr virus (EBV) and cytomegalovirus (CMV) harbor viral IL-10 mimics (ebvlL-10 and cmvlL-10) in their genomes that activate the IL-10 signaling complex, resulting in overlapping and distinct biological properties. In the past funding period, we determined crystal structures of clL-10, cmvlL-10, and ebvlL-10 bound to the high affinity IL-10R1 chain. In this proposal we will use surface plasmon resonance, site-directed mutagenesis, NMR spectroscopy, X-ray crystallography, and FRET methods to study cellular and viral IL-10 receptor interactions. These studies will be complemented by the analysis of the cellular IL-10 homologs IL- 22 and IL-20. The long term goal of this proposal is to derive a quantitative structural/computational model of IL-10 family signaling that might explain how cellular and viral IL-10s shape immune responses and allow the rational design of cytokine therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047300-09
Application #
7816941
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Leitner, Wolfgang W
Project Start
2000-04-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
9
Fiscal Year
2010
Total Cost
$352,057
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Logsdon, Naomi J; Eberhardt, Meghan K; Allen, Christopher E et al. (2011) Design and analysis of rhesus cytomegalovirus IL-10 mutants as a model for novel vaccines against human cytomegalovirus. PLoS One 6:e28127
Yoon, Sung-Il; Jones, Brandi C; Logsdon, Naomi J et al. (2010) Structure and mechanism of receptor sharing by the IL-10R2 common chain. Structure 18:638-48

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