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Tumor necrosis factor-alpha is not essential in endotoxin induced eye inflammation: studies in cytokine receptor
J T Rosenbaum1, Y B Han, J M Park
1Casey Eye Institute, Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland 97201-4197, USA.
Objective:
Anterior uveitis frequently occurs in association with specific systemic inflammatory diseases. Interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathogenesis of these diseases. We evaluate the need for these cytokines in a model of anterior uveitis.
Methods:
Endotoxin was injected into the vitreous of mice deficient in IL-1 receptor type I, TNF receptors p55 and p75, both IL-1R1 and TNFR p55, or controls. 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 separate experiments or in the combined data (p = 0.8). The number of infiltrating cells was significantly reduced in 2 of 4 experiments with IL-1R1 deficient 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 deficient 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 levels for IL-1-alpha, IL-10, TNF-alpha, IL-1 receptor antagonist, and inducible nitric oxide synthase.
Conclusions:
IL-1 appears to have a more pivotal role in endotoxin induced uveitis than TNF-alpha, although neither cytokine is essential. Deletion of receptors for both cytokines has the most consistent effect, which is in accord with the hypothesis that these cytokines are, at least in part, functionally redundant.
