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. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Leitner, Wolfgang W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Schools of Medicine
United States
Zip Code
Eberhardt, Meghan K; Deshpande, Ashlesha; Fike, Joseph et al. (2016) Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection. J Virol 90:9920-9930
Walter, Mark R (2014) The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol 380:191-212
Deshpande, Ashlesha; Putcha, Balananda-Dhurjati Kumar; Kuruganti, Srilalitha et al. (2013) Kinetic analysis of cytokine-mediated receptor assembly using engineered FC heterodimers. Protein Sci 22:1100-8
Eberhardt, Meghan K; Deshpande, Ashlesha; Chang, W L William et al. (2013) Vaccination against a virus-encoded cytokine significantly restricts viral challenge. J Virol 87:11323-31
Logsdon, Naomi J; Deshpande, Ashlesha; Harris, Bethany D et al. (2012) Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines. Proc Natl Acad Sci U S A 109:12704-9
Logsdon, Naomi J; Allen, Christopher E; Rajashankar, Kanagalaghatta R et al. (2012) Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex. Acta Crystallogr Sect F Struct Biol Cryst Commun 68:89-92
Yoon, Sung Il; Jones, Brandi C; Logsdon, Naomi J et al. (2012) Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties. J Biol Chem 287:26586-95
Eberhardt, Meghan K; Chang, W L William; Logsdon, Naomi J et al. (2012) Host immune responses to a viral immune modulating protein: immunogenicity of viral interleukin-10 in rhesus cytomegalovirus-infected rhesus macaques. PLoS One 7:e37931
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

Showing the most recent 10 out of 32 publications