Interferon‐α prevents endotoxin‐induced mortality in mice

Abstract

Endotoxins, the lipopolysaccharide (LPS) moieties on the bacterial cell wall, cause many of the pathological features of Gram-negative septicemia. Tumor necrosis factor (TNF), primarily a product of monocyte/macrophages, has been shown to mediate many of the pathophysiological effects of endotoxin. Kupffer cells, the largest macrophage population in the body, release TNF when stimulated by LPS in vitro. A recombinant human hybrid interferon-α A/D (rIFN-α) markedly inhibited this LPS-elicited TNF production by Kupffer cells. The effects of rIFN-α were further tested in C57BL/6 mice receiving a lethal dose (400 μg/mouse) of LPS. All LPS-treated mice died within 2 days. Pretreatment with rIFN-α 1 h before LPS challenge improved the survival at 3 days to 22% (5/23, p < 0.04). In contrast, rIFN-α was more effective when administered 20 min after LPS injection, increasing the survival rate to 81% (13/16, p < 0.0001). TNF mRNA expression in the liver and spleen 50 min after LPS challenge, and plasma TNF 1.5 h after LPS were also reduced by either pretreatment or post-treatment with rIFN-α. Subsequently, experiments were carried out to test the efficacy of delayed rIFN-α treatment. A significant protective effect was still apparent when rIFN-α was administered 6, 10 and even 14 h (81%, 62% and 28% survival, respectively) after LPS challenge when serum TNF levels had already returned to near baseline. These experimental results suggest that rIFN-α might have a therapeutic potential for the prevention and treatment of the deleterious effects associated with endotoxemia besides mechanisms initially blocking TNF production.