CYTOKINE FORMATION WITHIN RAT GLOMERULI DURING EXPERIMENTAL ENDOTOXEMIA

Increasing evidence supports a role of cytokines, tumor necrosis facto r alpha (TNFalpha), 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 functi on. Thus, this study investigates the chronology of cytokine expressio n in glomeruli isolated from normal rats or rats given iv lipopolysacc haride injections. Detectable levels of TNFalpha could be found in glo meruli isolated from normal rats as assessed by L-929 fibroblast lytic assay and ELISA. Glomeruli isolated from rats given lipopolysoccharid e transiently released increased amounts of TNFalpha in relation to th e dose of lipopolysaccharide (10 to 500 mug/kg body wt) and the lag pe riod between lipopolysaccharide injection and glomerular isolation (20 to 120 min). TNFalpha was released in similar amounts by glomeruli fr om normal rats that were exposed in vitro to lipopolysaccharide challe nge (0.01 to 10 mug/mL), indicating that lipopolysaccharide had direct effects on the release of TNFalpha from glomerular cells. These cells consisted mainly of resident cells because reduction of glomerular in filtration by bone marrow-derived cells after the irradiation of norma l rats did not affect TNFalpha release. Glomerular IL-1 and IL-6 produ ction was evaluated by specific bioassays under identical conditions. No IL-1 activity could be detected in the medium or within the glomeru lar cells at any time within 120 min after lipopolysaccharide injectio n. By contrast, glomerular IL-6 production was induced after lipopolys accharide challenge both in vivo and in vitro. Specific neutralization of TNFalpha did not affect IL-6 production, whereas neutralization of IL-6 slightly enhanced TNFalpha release. Thus, these results suggest that in endotoxin-induced acute renal failure: (1) TNFalpha and IL-6 a re produced by glomeruli in response to lipopolysaccharide, and (2) TN Falpha may possibly contribute to the development of glomerular hemody namic changes as suggested by its time course of production.