Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis. BMC Immunol 2015 May 12;16:28
Date
05/13/2015Pubmed ID
25962726Pubmed Central ID
PMC4427938DOI
10.1186/s12865-015-0091-2Scopus ID
2-s2.0-84929172594 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP), widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels the overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE).
METHODS: In the present study, we conducted an intensive computational docking analysis to identify novel E-FABP inhibitors for regulation of immune cell functions and for treatment of EAE.
RESULTS: We demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] bound to the lipid binding pocket of E-FABP and enhanced the expression of peroxisome proliferator-activating receptor (PPAR) γ. Further in vitro experiments showed that EI-03 regulated DC functions by inhibition of TNFα production while promoting IL-10 secretion. Moreover, EI-03 treatment counterregulated T cell balance by decreasing effector T cell differentiation (e.g. Th17, Th1) while increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in mouse models.
CONCLUSIONS: Taken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.
Author List
Rao E, Singh P, Li Y, Zhang Y, Chi YI, Suttles J, Li BAuthor
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Differentiation
Cytokines
Dendritic Cells
Drug Evaluation, Preclinical
Encephalomyelitis, Autoimmune, Experimental
Fatty Acid-Binding Proteins
Mice, Inbred C57BL
Molecular Docking Simulation
Molecular Targeted Therapy
Neoplasm Proteins
