ENHANCED RELEASE OF INTERLEUKIN-10 AND SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTORS AS NOVEL PRINCIPLES OF METHYLXANTHINE ACTION IN MURINE MODELS OF ENDOTOXIC-SHOCK

The immunomodulating capacity of the methylxanthine A802715 5-hydroxy- 5-methyl)hexyl-3-methyl-7-propylxanthin) was investigated in various m urine models of endotoxemia and compared with that of the chemically r elated reference compound pentoxifylline. At a dose of 180 mg/kg both compounds protected mice against a lethal shock dose of lipopolysaccha ride (LPS) (5 mg/kg) in nonsensitized mice and against LPS (5 mu g/kg) -initiated liver failure in D-galactosamine (700 mg/kg) sensitized ani mals. The methylxanthines attenuated systemic release of endogenous tu mor 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 le vels 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 l iver injury due to intravenous injection of recombinant TNF in D-galac tosamine-sensitized mice. In primary cultures of murine hepatocytes, A 802715 (500 mu M) as well as other cAMP-raising compounds conferred pr otection from TNF-cytotoxicity. We concluded that, in addition to a di rect target cell protection via an increase in intracellular cAMP, met hylxanthines prevented the systemic toxicity of LPS in mice by a furth er principle, i.e., by a shift of the humoral response to LPS in favor of an enhanced release of immunosuppressive cytokines.