Adenosine and a related carbocyclic nucleoside analogue selectively inhibit tumor necrosis factor-alpha production and protect mice against endotoxin challenge.
Adenosine (ADO) and its structurally related analogues are known to regulate the activities of immune and inflammatory cells, including a number of key functions of mononuclear phagocytes. In this study ADO and the synthetic ADO analogue MDL201112 inhibited TNF-alpha, but not IL-1, production by activated mouse peritoneal macrophages and the macrophage-like cell lines J774 and RAW-264. Northern blot analysis indicated that MDL201112 selectively inhibited the expression of steady-state TNF-alpha RNA in LPS+IFN-gamma-activated J774 and RAW-264 cells. This effect could not be attributed to changes in TNF-alpha RNA stability. In contrast, ADO had no effect on RNA levels for TNF-alpha and IL-1, suggesting that ADO acts at a post-transcriptional biosynthetic step. To determine whether either compound inhibited TNF-alpha-mediated inflammatory responses, mice were treated with ADO or MDL201112 and challenged with a lethal dose of endotoxic LPS and D-galactosamine, an hepatotoxin that sensitizes mice to lethal LPS challenge. A single i.p. injection of MDL201112 (100 mg/kg) protected over 90% of the mice, whether injected 1 h before or at the time of LPS challenge. MDL201112 also inhibited the appearance of TNF-alpha in the serum of LPS-challenged animals. The compound did not block D-galactosamine sensitization nor did it prevent lethality caused by the injection of rTNF-alpha. ADO failed to protect animals against endotoxin lethality, most likely due to the rapid metabolism of the nucleoside in vivo. These results establish ADO and MDL201112 as potent inhibitors of TNF-alpha biosynthesis and suggest that MDL201112 or similar analogues warrant further study as potential agents for the treatment of endotoxin shock and other diseases in which TNF-alpha plays an important pathogenic role.
Parmely
M J
MJ
Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160-7420.
Zhou
W W
WW
Edwards
C K
CK
Borcherding
D R
DR
Silverstein
R
R
Morrison
D C
DC
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C082151:3-(6-amino-9H-purin-9-yl)-cyclopentanol; D016207:Cytokines; D004731:Endotoxins; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000225:Adenine; D000241:Adenosine