Tumor necrosis factor-alpha is not essential in endotoxin induced eye inflammation: Studies in cytokine receptor deficient mice

Objective. Anterior uveitis frequently occurs in association with specific systemic inflammatory diseases. Interleukin 1 (IL-1) and tumor necrosis fac tor-alpha (TNF-alpha) have been implicated in the pathogenesis of these dis eases. We evaluate the need for these cytokines in a model of anterior uvei tis. Methods. Endotoxin was injected into the vitreous of mice deficient in IL-1 receptor type 1, TNF receptors p55 and p75, both IL-1R1 and TNFR p55, or c ontrols. Eyes were harvested after 24 h for histology and IL-6 bioassays or after 3 h for reverse transcriptase-polymerase chain reaction analysis of mRNA for specific cytokines or enzymes. Results. No significant difference in the number of infiltrating cells was found in TNFR p55/p75 deficient mice compared to controls in any of 4 separ ate experiments or in the combined data (p = 0.8). The number of infiltrati ng cells was significantly reduced in 2 of 4 experiments with IL-1R1 defici ent mice (p < 0.001 based on combined data from 4 studies). IL-1R1/TNFR p55 deficient mice had a reduction in infiltrating cells in 2 of 3 experiments (p < 0.001 based on combined data from all studies). IL-6 levels were not significantly reduced in either of 2 experiments with TNFR p55/p75 deficien t mice, but were reduced in one of 2 experiments with IL-1R1(-/-) mice (p = 0.02) and in one experiment with IL-1R1/TNFR p55 deficient mice (p = 0.01) , In response to endotoxin, all 3 receptor deficient lines increased mRNA l evels for IL-1-alpha, IL-10, TNF-alpha, IL-1 receptor antagonist, and induc ible nitric oxide synthase. Conclusions. IL-I appears to have a more pivotal role in endotoxin induced uveitis than TNF-a, although neither cytokine is essential. Deletion of rec eptors for both cytokines has the most consistent effect, which is in accor d with the hypothesis that these cytokines are, at least in part, functiona lly redundant.