Effects of an S-adenosyl-L-homocysteine hydrolase inhibitor on murine macrophage activation and function.
The S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor MDL 28,842 has been demonstrated to be a potent inhibitor of T-cell activation, both in vitro and in vivo. Although the inhibition of T cells in vitro was independent of macrophages, the direct effect of MDL 28,842 on macrophages is unknown. In this report the effects of MDL 28,842 on macrophage cytokine production, cell-surface antigen expression, and antigen processing and presentation were examined. Lipopolysaccharide (LPS) stimulation of IL-1 synthesis by peritoneal macrophages was not effected by MDL 28,842 using cells obtained from B10.A and B10.B mice and weakly inhibited using cells from BALB/C mice (IC50 > 10 microM). In contrast, TNF-alpha synthesis by BALB/C macrophages was inhibited by MDL 28,842 with an IC50 < 0.1 microM. B10.A and B10.B macrophages did not produce detectable TNF-alpha in response to LPS in this system. Treatment with 1-10 microM MDL 28,842 resulted in a modest decrease in major histocompatibility complex class II (MHC-II) determinant expression by Interferon-gamma-activated macrophages. The expression of other cell-surface markers was not altered in the presence of MDL 28,842. The processing of antigen and its presentation by MHC class-II-positive macrophages to a T-cell hybridoma was also not affected by incubation with MDL 28,842.)
Lambert
L E
LE
Marion Merrell Dow Research Institute, Cincinnati, OH 45215, USA.
Frondorf
K A
KA
Berling
J S
JS
Wolos
J A
JA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000954:Antigens, Surface / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C065189:4',5'-didehydro-5'-deoxy-5'-fluoroadenosine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine