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.