Mediators of the ocular inflammatory response to interleukin-1β plus tumor necrosis factor-α

Abstract

• Background: Intravitreal injection of marginally inflammatory doses of interleukin-1β and tumor necrosis factor-α (IL-1 β/TNFα) has been shown to produce intraocular inflammation distinctly different from that induced by higher intravitreal doses of either IL-1 or TNFα. Since cyclooxygenase inhibitors and platelet-activating factor (PAF)-receptor antagonists can reduce IL-1- or TNFα-induced uveitis, the present investigation was undertaken to determine whether cyclooxygenase metabolites of arachidonic acid and PAF are important mediators of IL-1β/TNFα-induced uveitis.

• Methods: The cyclooxygenase inhibitor indomethacin and two structurally dissimilar PAF-receptor antagonists, SRI 63-441 and WEB 2086, were used to investigate the importance of cyclooxygenase metabolites and PAF in IL-1β/TNFα-induced uveitis.

• Results: Based upon the effectiveness of indomethacin, the anterior uveitis induced by IL-1β/TNFα could be divided into two phases; a primary phase dependent upon generation of cyclooxygenase metabolites (the first 24 h) and a secondary phase largely independent of cyclooxygenase metabolite production (24–48 h). Posterior uveitis was also apparent at 48 h and was reduced by indomethacin. SRI 63-441 reduced the anterior uveitis at 24 h and to a lesser extent at 48 h; it also reduced the posterior uveitis at 48 h. However, although WEB 2086 was as effective as SRI 63-441 in reducing PAF-induced platelet aggregation, ex vivo, it did not significantly reduce IL-1β/TNFα-induced uveitis.

• Conclusions: Although the findings do not support an important role for PAF in TNFa/IL-1β-induced uveitis, it cannot be ruled out that more intensive treatment with a specific and long-acting PAF-receptor antagonist might yield more positive results.