The immunomodulating capacity of the methylxanthine A802715 (5-hydroxy-5-methyl)hexyl-3-methyl-7-propylxanthin) was investigated in various murine models of endotoxemia and compared with that of the chemically related reference compound pentoxifylline. At a dose of 180 mg/kg both compounds protected mice against a lethal shock dose of lipopolysaccharide (LPS) (5 mg/kg) in nonsensitized mice and against LPS (5 micrograms/kg)-initiated liver failure in D-galactosamine (700 mg/kg)-sensitized animals. The methylxanthines attenuated systemic release of endogenous tumor necrosis factor (TNF) and interferon-gamma during endotoxic shock, and potently up-regulated early production of circulating interleukin-10 and interleukin-6. Treatment of mice with A802715 alone induced levels of circulating soluble TNF receptors (sTNF-R p55 and p75) 3- to 4-fold higher than those of controls. This increase was additive to the one elicited by LPS. Moreover, pentoxifylline and A802715 prevented liver injury due to intravenous injection of recombinant TNF in D-galactosamine-sensitized mice. In primary cultures of murine hepatocytes, A802715 (500 microM) as well as other cAMP-raising compounds conferred protection from TNF cytotoxicity. We concluded that, in addition to a direct target cell protection via an increase in intracellular cAMP, methylxanthines prevented the systemic toxicity of LPS in mice by a further principle, i.e., by a shift of the humoral response to LPS in favor of an enhanced release of immunosuppressive cytokines.