Involvement of TNFα, IL-1β and IL-1 receptor antagonist in LPS-induced rabbit uveitis

The objective of the study was to investigate involvement of TNF alpha, IL-1 beta and IL-1 receptor antagonist (IL-1Ra) in lipopolysaccharide (LPS)-induced uveitis. Intravitreal injection of LPS (100 ng) to rabbits induced a massive leukocyte infiltration and protein leakage into the aqueous humor. Aqueous leukocyte counts and protein levels reached a peak 24 hr after this injection. The peak concentrations of aqueous TNF alpha (230 +/- 37 pg ml(-1), at 9 hr) and IL-1 beta (185 +/- 80 pg ml(-1), at 18 hr) preceded peak levels of aqueous leukocyte counts and protein levels. In contrast, the levers of aqueous IL-1Ra peaked at 48 hr (12239 +/- 1964 pg ml(-1)) and a fairly high concentration of IL-1Ra remained when the inflammatory reactions subsided. Immunohistochemistry and leukocyte-depletion studies showed that infiltrating leukocytes were the major cellular sources of aqueous TNF alpha, IL-1 beta and IL-1Ra. Intravitreal injection of homologous TNF alpha (0.1-1.5 mu g) or IL-1 beta (0.5-5 ng) reproduced a rapid Ieukocyte infiltration and protein leakage. Administration of anti-TNF alpha mAb (10 mu g) suppressed the number of LPS-induced infiltrating neutrophils by 50%, mononuclear cells by 58%, and protein leakage by 42%. Administration of rabbit IL-1Ra (10 mu g) also suppressed neutrophil influx by 78%, however, neither mononuclear cell influx nor protein leakage was inhibited by rabbit IL-1Ra. Go-administration of the two inhibitors enhanced inhibition of neutrophil infiltration to 88%, and protein leakage to 64%. We conclude that TNF alpha, and IL-1 beta are the principal mediators of LPS-induced uveitis. Our observations also suggest that endogenous IL 1Ra may down-regulate inflammatory reactions. (C) 1998 Academic Press Limited.