Cytokine formation within rat glomeruli during experimental endotoxemia

Abstract

Increasing evidence supports a role of cytokines, tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1), and IL-6 in the development of endotoxin-induced acute renal failure. Several activities of these cytokines require a local rather than a systemic production and function. Thus, this study investigates the chronology of cytokine expression in glomeruli isolated from normal rats or rats given iv lipopolysaccharide injections. Detectable levels of TNFα could be found in glomeruli isolated from normal rats as assessed by L-929 fibroblast lytic assay and ELISA. Glomeruli isolated from rats given lipopolysaccharide transiently released increased amounts of TNFα in relation to the dose of lipopolysaccharide (10 to 500 μg/kg body wt) and the lag period between lipopolysaccharide injection and glomerular isolation (20 to 120 min). TNFα was released in similar amounts by glomeruli from normal rats that were exposed in vitro to lipopolysaccharide challenge (0.01 to 10 μg/mL), indicating that lipopolysaccharide had direct effects on the release of TNFα from glomerular cells. These cells consisted mainly of resident cells because reduction of glomerular infiltration by bone marrow-derived cells after the irradiation of normal rats did not affect TNFα release. Glomerular IL-1 and IL-6 production was evaluated by specific bioassays under identical conditions. No IL-1 activity could be detected in the medium or within the glomerular cells at any time within 120 min after lipopolysaccharide injection. By contrast, glomerular IL-6 production was induced after lipopolysaccharide challenge both in vivo and in vitro. Specific neutralization of TNFα did not affect IL-6 production, whereas neutralization of IL-6 slightly enhanced TNFα release. Thus, these results suggest that in endotoxin-induced acute renal failure: (1) TNFα and IL-6 are produced by glomeruli in response to lipopolysaccharide, and (2) TNFα may possibly contribute to the development of glomerular hemodynamic changes as suggested by its time course of production.