Premium
In Vitro and In Vivo Inhibition of Immunoglobulin Secretion by the Immunosuppressive Compound HR325 is Reversed by Exogenous Uridine
Author(s) -
Thomson T. A.,
SpinellaJaegle S.,
Francesconi E.,
Meakin C.,
Millet S.,
Flao K. L.,
Hidden H.,
Ruuth E.
Publication year - 2002
Publication title -
scandinavian journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.934
H-Index - 88
eISSN - 1365-3083
pISSN - 0300-9475
DOI - 10.1046/j.1365-3083.2002.01107.x
Subject(s) - uridine , in vivo , dihydroorotate dehydrogenase , in vitro , pyrimidine metabolism , antibody , microbiology and biotechnology , secretion , biology , splenocyte , immunoglobulin g , chemistry , biochemistry , immunology , rna , enzyme , purine , gene
The objective was to demonstrate that the immunosuppressive agent HR325 (an inhibitor of dihydroorotate dehydrogenase, DHODH) inhibits immunoglobulin (Ig) secretion both in vitro and in vivo and that this effect can be reversed with exogenous uridine. In vitro, Ig secretion from mouse splenocytes was induced by lipopolysaccharide (LPS) for 5 days. HR325 inhibited the secretion of IgM and IgG with IC50values of 2.5 and 2 µm, respectively. Adding uridine (50 µm) increased these values to 70 and 60 µm, respectively. Similarly, the IC50values of another DHODH inhibitor, brequinar sodium, were also attenuated by uridine from 0.04 to 1 µmfor IgM, and 0.012 to 10 µm for IgG. HR325 (and a structural analogue A771726) inhibited LPS‐induced kappa light‐chain cell surface expression on 70Z/3 cells, a property also reversed by uridine. In vivo, the secondary anti‐sheep red blood cell (SRBC) antibody response (unaffected by uridine alone) was inhibited by HR325 and brequinar with respective ID50values of 38 and 0.6 mg/kg per oral (p.o.). Immunosuppression with HR325 (50 mg/kg) and brequinar (1 mg/kg) was abrogated by uridine. Uridine had no effect on cyclophosphamide‐induced (10 mg/kg p.o.) immunosuppression. These data are consistent with the immunosuppressive mechanism of HR325 being the result of pyrimidine depletionin vitroandin vivo .