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


RESULTS
Based upon the effectiveness of indomethacin, the anterior uveitis induced by IL-1 beta/TNF alpha 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-1 beta/TNF alpha-induced uveitis.


CONCLUSIONS
Although the findings do not support an important role for PAF in TNF alpha/IL-1 beta-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.
Fleisher
L
L
North Carolina State University, College of Veterinary Medicine, Raleigh 27606, USA.
Ferrell
J
J
McGahan
C
C
D000818:Animals; D007213:Indomethacin / Q000627:therapeutic use; D007375:Interleukin-1 / Q000633:toxicity*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014606:Uveitis, Anterior / Q000276:immunology / Q000517:prevention & control*; D015866:Uveitis, Posterior / Q000276:immunology / Q000517:prevention & control*
D007375:Interleukin-1; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D007213:Indomethacin